Dicarbonyl derivatives and methods of use

ABSTRACT

Derivatives of dicarbonyl compounds having antitumor and antibiotic activity which can be used as anticancer agents.

CROSS-REFERENCE TO RELATED APPLICATIONS

This patent application is a continuation of copending U.S. patentapplication Ser. No. 11/939,909, filed Nov. 14, 2007, which now hasallowed claims and which is incorporated by reference. This patentapplication claims the benefit of U.S. Provisional Patent ApplicationNo. 60/866,341, filed Nov. 17, 2006, which is incorporated by reference.

This patent application claims the benefit of U.S. Provisional PatentApplication No. 60/866,341, filed Nov. 17, 2006, which is incorporatedby reference.

BACKGROUND OF THE INVENTION

It has been reported that novel natural products Lomaiviticins A and B,isolated from the actinomycete Micromonospora lomaivitiensis, are potentantitumor and antibiotic agents (He, H. et al., J. Am. Chem. Soc. 2001,123, 5362-5363). These lomaiviticins are potent DNA cleaving agents within vitro cytotoxicity against a number of cell lines with IC₅₀ valuesranging from 0.01 to 98 ng/mL. Inspection of the structures of thelomaiviticins leads to the recognition of the following structuralelements: (a) the diazo groups; (b) the tetracyclic framework of themonomeric unit; (c) the carbohydrate moieties; (d) the hindered centralcarbon-carbon bond linking the two units; (e) the readily labileβ-alkoxy functionality at C-3 and C-3′ and (f) the dicarbonyl corestructure in lomaivitivin A.

On the other hand, patents revealed that benzoylacrylamide derivatives,containing dicarbony group, have intensive tyrosine kinase inhibitingactivity and can be used as anticancer agents (U.S. Pat. No. 5,618,829;U.S. Pat. No. 4,130,661; EP Patent Application No. 0608897A2). It iswell known that tyrosine kinase plays an important role in intercellularsignal transduction and cell differentiation or growth. Accordingly,failure of control of tyrosine kinase activity in cells disordersintercellular signal transduction and causes abnormal celldifferentiation/growth, which is considered to be directly responsiblefor the development of various diseases. In particular, it is known thattyrosine kinase is significantly associated with disorderly overgrowthof cancer cells. It has been proposed that an agent specificallyinhibiting tyrosine kinase activity would be an anti-cancer agent havingminor side-effects and exerting its therapeutic effect through novelmechanisms.

The recognitions of the dicarbonyl group in the novel natural productlomaiviticin A as one of the core structures to exert its anticanceractivity, together with the novel tyrosine kinase inhibitory activity ofbenzoylacrylamide derivatives, lead inventors of the present inventionto devote them to a study for developing a new class of dicarbonylderivatives. Accordingly, the purpose of the present invention is toprovide a family of novel compounds useful for suppressing the growth ofcancer cells, which compounds are easily available, exhibit specific andintensive activity in inhibiting tyrosine kinase of the growth factorreceptor, and show negligible side-effects compared with previouslyknown anti-cancer agents.

Several reports have disclosed the preparation of some dicarbonylderivatives. The synthesis of 1,4-diketones have been disclosed in thepublication by (a) Rathke, M. W. et al (J. Am. Chem. Soc. 1971, 93,4605-4606); (b) Dessau, R. M et al (J. Org. Chem. 1974, 39, 3457-3459);(c) Ito, Y. et al (J. Am. Chem. Soc. 1975, 97, 2912-2914); (d) Ito, Y.et al (J. Am. Chem. Soc. 1977, 99, 1487-1493); (e) Frazier, R. H et al(J. Org. Chem. 1980, 45, 5408-5411); (f) Paquette, L. A. et al (J. Org.Chem. 1995, 60, 7277-7283). For example,[4,4′-bycyclohexenyl]-3,3′-dione can be prepared from2-cyclohexene-1-one, which was converted to its enolate with LDA andoxidized with ferric chloride (J. Org. Chem. 1980, 45, 5408-5411).Copper chloride and silver oxide have also been used as the oxidativereagents (J. Am. Chem. Soc. 1977, 99, 1487-1493; J. Am. Chem. Soc. 1975,97, 649). The syntheses of benzoylacrylamide derivatives have beendisclosed in patents (U.S. Pat. No. 5,618,829; U.S. Pat. No. 4,130,661;EP Patent Application No. 0608897A2). For example,3,4-dimethoxyacetophenone reacted with glyoxylic acid monohydrate underreflux provided the corresponding substituted benzoylacrylic acid, whichcan be converted to various amides (U.S. Pat. No. 5,618,829). Thesynthesis of oxime, such as oxime derivatives of radicicol, was reportedfor their preparation (Ikuina, Y. et al, J. Med. Chem. 2003, 46,2534-2541). The preparation of isoxazoles were also revealed (Hansen, T.V. et al, J. Org. Chem. 2005, 70, 7761-7764; Parhi, A. K. et al, Org.Lett. 2004, 6, 3063-3065; Himo, F. et al, J. Am. Chem. Soc. 2005, 127,210-216; WO 2004/072051 A1).

SUMMARY OF THE INVENTION

Accordingly, it is an objective of the present invention to provide anantitumor agent comprising a dicarbonyl derivative as described informula (I), pharmaceutically-acceptable formulations thereof, andmethods for using such derivatives (alone and in combination with othertherapeutic agents) against different types of tumors. The combinationtherapy decribed herein may be provided by the preparation of thedicarbonyl derivative of formula (I) and the other therapeutic agent asseparate pharmaceutical formulations followed by the administrationthereof to a patient simultaneously, semi-simultaneously, separately orover regular intervals.

Additional objects and advantages of the present invention will be setforth in part in the description which follows, and in part will beapparent from the description, or may be learned by practice of thepresent invention.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the present invention are those dicarbonyl derivativesof formula (I):

wherein:

R₁, R₂, R₃, R₄, R₅, and R₆ are independently: a hydrogen atom or analkyl, alkoxy, alkylthiol, alkylamino, alkenyl, alkynyl group comprising1 to 30 carbon atoms and which is unsubstituted or substituted by atleast one of the substituents (a) as defined below;

an aryl group comprising 6 to 14 ring atoms and which is unsubstitutedor substituted by at least one of the substituents (b) as defined below;

a heterocyclic group which has 5 or 6 ring atoms of which from 1 to 3are nitrogen and/or oxygen and/or sulphur hetero-atoms, saidheterocyclic group being unsubstituted or substituted by at least one ofthe substituents (c) as defined below;

X and Y are O, NR′ or S; and

R¹ represents a group of substituents (a) as defined below; whereinsubstituent (a) is

a hydroxy group, an alkoxy group comprising from 1 to 20 carbon atomsand which are unsubstituted or substituted by at least one alkoxy groupcomprising from 1 to 4 carbon atoms and/or an alkylthio group comprisingfrom 1 to 4 carbon atoms; an aryl group comprising from 6 to 14 ringatoms and which are unsubstituted or substituted by at least one of thesubstituents (b) as defined below; or a group of formula —NR¹R²,—CONR¹R², —OR¹ or —OCON R¹R², wherein R¹ and R² are the same ordifferent and are a hydrogen atom; an alkyl, alkoxy, alkenyl, or alkynylgroup comprising from 1 to 20 carbon atoms, which group is unsubstitutedor substituted by at least one of substituents (b) other than the groupof formula —NR¹R², —CONR¹R², —OR¹ and —OCON R¹R² or by an aryl group inwhich the aryl moiety comprises 6 to 10 ring carbon atoms and isunsubstituted or substituted by at least one of the substituents (b) asdefined below; or a heterocyclic group being unsubstituted orsubstituted by at least one of the substituents (c) as defined below;wherein substituent (b) is

a hydroxy group; a cyano group; a mercapto group; a halogen atom; analkyl group comprising from 1 to 8 carbon atoms;

a group of formula —NR¹R², —CONR¹R² or —OCON R¹R², wherein R¹ and R² areas defined above;

an alkylthio group comprising 1 to 20 carbon atoms;

a heterocyclic group comprising 5 or 6 ring atoms of which from 1 to 3are nitrogen and/or oxygen and/or sulphur hetero-atoms, saidheterocyclic group being unsubstituted or substituted by at least one ofthe substituents (c) as defined below; and wherein substituent (c) is

a hydroxy group; a halogen atom, a cyano group; an alkyl groupcomprising 1 to 8 carbon atoms; an aryl group comprising 6 to 10 ringatoms and which are unsubstituted or substituted by at least one of thesubstituents (b) as defined above;

a group of formula —NR¹R², —CONR¹R² or —OCON R¹R², wherein R¹ and R² areas defined above;

an aryl group in which the aryl moiety comprises 6 to 10 ring carbonatoms and is unsubstituted or substituted by at least one of thesubstituents (b) as defined above;

an aliphatic carboxylic acyl group comprising 1 to 20 carbon atoms;

an aromatic carboxylic acyl group in which the aryl moiety comprises 6to 10 ring carbon atoms and is unsubstituted or substituted by at leastone of the substituents (b) as defined above.

The present invention also provides, in a preferred embodiment, acompound or pharmaceutically acceptable salt thereof having the formula(I)

wherein

R₁, R₂, R₃, R₄, R₅, and R₆ are independently a hydrogen atom or analkyl, alkenyl, alkynyl, or aryl comprising 1 to 30 carbon atoms andwhich is unsubstituted or substituted by at least one of hydroxy, cyano,mercapto, halogen, —OR₇, SR₇, —NR₇R₈, —CONR₇R₈, or —OCONR₇R₈, wherein

-   -   R₇ and R₈ are independently a hydrogen atom; an alkyl, alkenyl,        or alkynyl comprising 1 to 20 carbon atoms; a cyclic or        heterocyclic group comprising 5 or 6 ring atoms of which from 0        to 3 are nitrogen and/or oxygen and/or sulphur heteroatoms, said        cyclic or heterocyclic group being unsubstituted or substituted        by at least one of hydroxy, cyano, mercapto, halogen, or an        alkyl group comprising 1 to 6 carbon atoms; and

X and Y are respectively O, NR₇ or S, wherein when X and Y are O, and ifR₂, R₄ are hydrogen, R₁-R₃ or both R₁-R₃ and R₅-R₆ form a cyclic or anacyclic alkenyl; and when X and Y are O, and if R₂, R₄ form a singlebond, R₁ is

wherein Ar is an aryl or heteroaryl.

The following definitions refer to the various terms used above andthroughout the disclosure.

The term “halogen” refers to fluoro, chloro, bromo or iodo atom.

The term “alkyl” refers to an alkyl, substituted or unsubstituted,straight or branched chain group, having from 1-30 carbon atoms.Illustrative of the alkyl group include the methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, 3-methylbutyl,2,2-dimethylpropyl, 1,1-dimethylpropyl, hexyl, 1-methylpentyl,4-methylpentyl, heptyl, 1-methylhexyl, 2-methylhexyl, 5-methylhexyl,3-ethylpentyl, octyl, 2-methylheptyl, 6-methylheptyl, 2-ethylhexyl,2-ethyl-3-methylpentyl, 3-ethyl-2-methylpentyl, nonyl, 2-methyloctyl,7-methyloctyl, 4-ethylheptyl, 3-ethyl-2-methylhexyl,2-ethyl-1-methylhexyl, decyl, 2-methylnonyl, 8-methylnonyl,5-ethyloctyl, 3-ethyl-2-methylheptyl, 3,3-diethylhexyl, undecyl,2-methyldecyl, 9-methyldecyl, 4-ethylnonyl, 3,5-dimethylnonyl,3-propyloctyl, 5-ethyl-4-methyloctyl, 1-pentylhexyl, dodecyl,1-methylundecyl, 10-methylundecyl, 3-ethyldecyl, 5-propylnonyl,3,5-diethyloctyl, tridecyl, 11-methyldodecyl, 7-ethylundecyl,4-propyldecyl, 5-ethyl-3-methyldecyl, 3-pentyloctyl, tetradecyl,12-methyltridecyl, 8-ethyldodecyl, 6-propylundecyl, 4-butyldecyl,2-pentylnonyl, pentadecyl, 13-methyltetradecyl, 10-ethyltridecyl,7-propyldodecyl, 5-ethyl-3-methyldodecyl, 4-pentyldecyl, 1-hexylnonyl,hexadecyl, 14-methylpentadecyl, 6-ethyltetradecyl, 4-propyltridecyl,2-butyldodecyl, heptadecyl, 15-methylhexadecyl, 7-ethylpentadecyl,3-propyltetradecyl, 5-pentyldodecyl, octadecyl, 16-methylheptadecyl,5-propylpentadecyl, nonadecyl, 17-methyloctadecyl, 4-ethylheptadecyl,icosyl, 18-methylnonadecyl, 3-ethyloctadecyl, henicosyl, docosinyl,tricosinyl, tetracosinyl and pentacosinyl groups.

The term “alkenyl” represents an alkenyl group having from 2 to 30carbon atoms and may be a straight or branched chain group. It may have1 or more, preferably from 2 to 6, double bonds. Examples of such groupsinclude the vinyl, allyl, 1-propenyl, isopropenyl, 2-methyl-1-propenyl,1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl,4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl,1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 8-nonenyl, 1-nonenyl,1-decenyl, 9-decenyl, 8-tridecenyl, cis-8-pentadecenyl,trans-8-pentadecenyl, 8-heptadecenyl, 8-heptadecenyl,8,11-heptadecadienyl, 8,11,14-heptadecatrienyl,4,7,11,14-nonadecatetraenyl and2,6-dimethyl-8-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1,3,5,7-nonatetraen-1-yl,cis-10-nonadecaenyl, 10,13-nonadecadienyl, cis-7,10,13-nonadecatrienyl,5,8,11,14-nonadecatetraenyl, nonadecapentaenyl.

The term “alkoxy” refers to an alkoxy group with 1 to 20 carbon alkylgroups, and the alkyl moiety thereof generally corresponds to the C₁-C₂₀alkyl groups described above and can be selected wherefrom. Examples ofsuch groups include the methoxy, ethoxy, propoxy, isopropoxy, butoxy,isobutoxy, sec-butoxy, t-butoxy, pentoxy, 3-methylbutoxy,2,2-dimethylpropoxy, 1,1-dimethylpropoxy, hexyloxy, 1-methylpentyloxy,4-methylpentyloxy, heptyloxy, 1-methylhexyloxy, 2-methylhexyloxy,5-methylhexyloxy, 3-ethylpentyloxy, octyloxy, 2-methylheptyloxy,6-methylheptyloxy, 2-ethylhexyloxy, 2-ethyl-3-methylpentyloxy,3-ethyl-2-methylpentyloxy, nonyloxy, 2-methyloctyloxy, 7-methyloctyloxy,4-ethylheptyloxy, 3-ethyl-2-methylhexyloxy, 2-ethyl-1-methylhexyloxy,decyloxy, 2-methylnonyloxy, 8-methylnonyloxy, 5-ethyloctyloxy,3-ethyl-2-methylheptyloxy, 3,3-diethylhexyloxy, undecyloxy,2-methyldecyloxy, 9-methyldecyloxy, 4-ethylnonyloxy,3,5-dimethylnonyloxy, 3-propyloctyloxy, 5-ethyl-4-methyloctyloxy,1-pentylhexyloxy, dodecyloxy, 1-methylundecyloxy, 10-methylundecyloxy,3-ethyldecyloxy, 5-propylnonyloxy, 3,5-diethyloctyloxy, tridecyloxy,11-methyldodecyloxy, 7-ethylundecyloxy, 4-propyldecyloxy,5-ethyl-3-methyldecyloxy, 3-pentyloctyloxy, tetradecyloxy,12-methyltridecyloxy, 8-ethyldodecyloxy, 6-propylundecyloxy,4-butyldecyloxy, 2-pentylnonyloxy, pentadecyloxy,13-methyltetradecyloxy, 10-ethyltridecyloxy, 7-propyldodecyloxy,5-ethyl-3-methyldodecyloxy, 4-pentyldecyloxy, 1-hexylnonyloxy,hexadecyloxy, 14-methylpentadecyloxy, 6-ethyltetradecyloxy,4-propyltridecyloxy, 2-butyldodecyloxy, heptadecyloxy,15-methylhexadecyloxy, 7-ethylpentadecyloxy, 3-propyltetradecyloxy,5-pentyldodecyloxy, octadecyloxy, 16-methylheptadecyloxy,5-propylpentadecyloxy, nonadecyloxy, 17-methyloctadecyloxy,4-ethylheptadecyloxy, icosyloxy, 18-methylnonadecyloxy, and3-ethyloctadecyloxy groups.

The term “aryl” and “heterocyclic” refers to an aromatic orheteroaromatic ring. The aryl ring can be substituted with substituentsselected from the group consisting of halogen, C₁-C₆ alkyl or C₁-C₆alkoxy, or alkyl amino. Examples include 4-chlorophenyl, 2-fluorophenyl,4-fluorophenyl, 3-flourophenyl, 4-methylphenyl, 4-ditrifluorohenyl,2-ethylphenyl, 3-n-propylphenyl, 4-isopropyl-phenyl, 4-n-butylphenyl,4-t-butylphenyl, 4-sec-butylphenyl, 4-dimethylaminophenyl,3,4-dimethylphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-isopropoxyphenyl,3-isobutoxyphenyl, 4-t-butoxyphenyl, 4-nitrophenyl, 2-furan, 2-pyridyl,3-pyridyl, 2-thiophenyl, 3-thiophenyl, 1-naphthyl, 2-naphthyl,2-indolyl, and the like, and the aryl moiety of aryl and arylcarbamoylhave the same meaning. Examples of the heterocyclic group include thefuryl, thienyl, pyrrolyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl,isoxazolyl, imidazolyl, pyrazolyl, pyranyl, pyrazinyl, pyridazinyl,pyrimidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl,thiazolidinyl, thiazolinyl, isothiazolinyl, imidazolidinyl,imidazolinyl, oxazolinyl, isoxazolinyl, oxazolidinyl, pyrazolidinyl,piperazinyl, dioxopiperazinyl, tetrahydropyrimidinyl,dihydropyridazinyl, morpholinyl, thiomorpholinyl, pyrrolidonyl,piperidonyl, pyridonyl, 2H-pyrrolyl, furazanyl and pyrazolinyl groups,especially the furyl, pyrrolyl, pyridyl, thiazolyl, isothiazolyl,oxazolyl, isoxazolyl, imidazolyl, pyridazinyl, pyrrolidinyl,thiazolinyl, isothiazolinyl, imidazolyl, piperazinyl, dioxopiperazinyl,morpholinyl, pyrrolidonyl and piperidonyl groups. Such groups may beunsubstituted or they may be substituted by at least one of substituents(c), defined above and exemplified below.

The teem “alkylamino” refers to a substituted derivative of ammonia,wherein one or two hydrogen of ammonia is replaced by an alkyl grouphaving 1 to 20 carbon, and the alkyl moiety thereof generallycorresponds to the C₁-C₂₀ alkyl groups described above and can beselected wherefrom. Examples of the alkylamino include the aremethylamino, ethylamino, propylamino, 1-methylethylamino, butylamino,isobutylamino, sec-butylamino, t-butylamino, pentylamino,3-methylbutylamino, 2,2-dimethylpropylamino, 1,1-dimethylpropylamino,hexylamino, 1-methylpentylamino, 4-methylpentylamino, heptylamino,1-methylhexylamino, 2-methylhexylamino, 5-methylhexylamino,3-ethylpentylamino, octylamino, 2-methylheptylamino,6-methylheptylamino, 2-ethylhexylamino, 2-ethyl-3-methylpentylamino,3-ethyl-2-methylpentylamino, nonylamino, N,N-dimethylamino, N,N-diethylamino, N,N-dipropylamino, N-methyl-N-ethylamino,N,N-dibutylamino, N-methyl-N-(1,1-dimethylethyl) amino, and like.

The term “alkylthio” refers to a thio group with 1 to 20 carbon alkylgroups, and the alkyl moiety thereof generally corresponds to the C₁-C₂₀alkyl groups described above and can be selected wherefrom. Examplesinclude the methylthio, ethylthio, propylthio, isopropylthio, butylthio,isobutylthio, sec-butylthio, t-butylthio, pentylthio, 3-methylbutylthio,2,2-dimethylpropylthio, 1,1-dimethylpropylthio, hexylthio,1-methylpentylthio, 4-methylpentylthio, heptylthio, 1-methylhexylthio,2-methylhexylthio, 5-methylhexylthio, 3-ethylpentylthio, octylthio,2-methylheptylthio, 6-methylheptylthio, 2-ethylhexylthio,2-ethyl-3-methylpentylthio, 3-ethyl-2-methylpentylthio, nonylthio,2-methyloctylthio, 7-methyloctylthio, 4-ethylheptylthio,3-ethyl-2-methylhexylthio, 2-ethyl-1-methylhexylthio, decylthio,1-pentylhexylthio, dodecylthio, octadecylthio, 16-methylheptadecylthio,nonadecylthio, 18-methylnonadecylthio and 3-ethyloctadecylthio groups;

The term “cycloalkyl” refers to alkyl group that has from 3 to 8 carbonatoms and may be unsubstituted or substituted. If it is substituted, itis substituted by at least one of substituents (c), defined above andexemplified below. Examples of such groups include the cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl and cyclooctyl groupsand substituted analogues thereof.

The term “cycloalkenyl” refers to a group that has from has from 5 to 8carbon atoms and may be unsubstituted or substituted. If it issubstituted, it is substituted by at least one of substituents (c),defined above and exemplified below. It has one or more, preferably 1 or2, more preferably 1, carbon-carbon double bond or bonds. Examples ofsuch groups include the 1-cyclopenten-1-yl, 2-cyclopenten-1-yl,1-cyclohexen-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl,1-cylohepten-1-yl, 2-cyclohepten-1-yl, 1-cycloocten-1-yl and3-cycloocten-1-yl groups and substituted analogues thereof.

The term “pharmaceutically acceptable salts” of the compounds of theinvention include those derived from pharmaceutically acceptableinorganic and organic acids and bases. Examples of suitable acidsinclude hydrochloric, hydrobromic, sulfuric, nitric, perchloric,fumaric, maleic, phosphoric, glycolic, gluconic, lactic, salicylic,succinic, toluene-p 10 sulfonic, tartaric, acetic, citric,methanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic,benzenesulfonic, 1,2 ethanesulfonic acid (edisylate),galactosyl-d-gluconic acid, and the like. Other acids, such as oxalicacid, while not themselves pharmaceutically acceptable, may be employedin the preparation of salts useful as intermediates in obtaining thecompounds of this invention and their pharmaceutically acceptable acid15 addition salts. Salts derived from appropriate bases include alkalimetal (e.g. sodium), alkaline earth metal (e.g. magnesium), ammonium andN—(C₁-C₄ alkyl)₄ ⁺ salts, and the like. Illustrative examples of some ofthese include sodium hydroxide, potassium hydroxide, choline hydroxide,sodium carbonate, and the like.

A number of compounds of formula I possess asymmetric carbons and cantherefore exist in racemic and optically active forms. Methods ofseparation of enantiomeric and diastereomeric mixtures are well known toone skilled in the art. The present invention encompasses any isolatedracemic or optically active form of compounds described in formula I,and uses thereof as described herein.

Examples of groups and atoms which may be included in substituents (a)are: hydroxy groups; chlorine, fluorine, bromine and iodine atoms; cyanogroup; mercapto groups; carboxy groups; alkoxy groups which have from 1to 20 carbon atoms and which are unsubstituted or are substituted by atleast one alkoxy group having from 1 to 4 carbon atoms and/or alkylthiogroup having from 1 to 4 carbon atoms, such as the methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, t-butoxy, pentyloxy,methoxymethoxy, 1-methoxyethoxy, 2-methoxyethoxy, butoxymethoxy,2-butoxyethoxy, 3-ethoxypropoxy, 3-methylbutoxy, 2,2-dimethylpropoxy,1,1-dimethylpropoxy, hexyloxy, 1-methylpentyloxy, 4-methylpentyloxy,heptyloxy, 1-methylhexyloxy, 2-methylhexyloxy, 5-methylhexyloxy,3-ethylpentyloxy, octyloxy, 2-methylheptyloxy, 6-methylheptyloxy,2-ethylhexyloxy, 2-ethyl-3-methylpentyloxy, 3-ethyl-2-methylpentyloxy,nonyloxy, 2-methyloctyloxy, 7-methyloctyloxy, 4-ethylheptyloxy,3-ethyl-2-methylhexyloxy, 2-ethyl-1-methylhexyloxy, decyloxy,2-methylnonyloxy, 8-methylnonyloxy, 5-ethyloctyloxy,3-ethyl-2-methylheptyloxy, 3,3-diethylhexyloxy, undecyloxy,2-methyldecyloxy, 9-methyldecyloxy, 4-ethylnonyloxy,3,5-dimethylnonyloxy, 3-propyloctyloxy, 5-ethyl-4-methyloctyloxy,1-pentylhexyloxy, dodecyloxy, 1-methylundecyloxy, 10-methylundecyloxy,3-ethyldecyloxy, 5-propylnonyloxy, 3,5-diethyloctyloxy, tridecyloxy,11-methyldodecyloxy, 7-ethylundecyloxy, 4-propyldecyloxy,5-ethyl-3-methyldecyloxy, 3-pentyloctyloxy, tetradecyloxy,12-methyltridecyloxy, 8-ethyldodecyloxy, 6-propylundecyloxy,4-butyldecyloxy, 2-pentylnonyloxy, pentadecyloxy,13-methyltetradecyloxy, 10-ethyltridecyloxy, 7-propyldodecyloxy,5-ethyl-3-methyldodecyloxy, 4-pentyldecyloxy, 1-hexylnonyloxy,hexadecyloxy, 14-methylpentadecyloxy, 6-ethyltetradecyloxy,4-propyltridecyloxy, 2-butyldodecyloxy, heptadecyloxy,15-methylhexadecyloxy, 7-ethylpentadecyloxy, 3-propyltetradecyloxy,5-pentyldodecyloxy, octadecyloxy, 16-methylheptadecyloxy,5-propylpentadecyloxy, nonadecyloxy, 17-methyloctadecyloxy,4-ethylheptadecyloxy, icosyloxy and 18-methylnonadecyloxy,3-ethyloctadecyloxy groups; aryl groups which have from 6 to 14 ringatoms and which are unsubstituted or which are substituted by at leastone of substituents (b), defined above and exemplified below, such asthe phenyl, 1-naphthyl, 2-naphthyl, fluorenyl, 1-anthryl and1-phenanthryl groups and substituted analogues thereof;

alkylthio groups having from 1 to 20 carbon atoms, such as themethylthio, ethylthio, propylthio, isopropylthio, butylthio,isobutylthio, sec-butylthio, t-butylthio, pentylthio, 3-methylbutylthio,2,2-dimethylpropylthio, 1,1-dimethylpropylthio, hexylthio,1-methylpentylthio, 4-methylpentylthio, heptylthio, 1-methylhexylthio,2-methylhexylthio, 5-methylhexylthio, 3-ethylpentylthio, octylthio,2-methylheptylthio, 6-methylheptylthio, 2-ethylhexylthio,2-ethyl-3-methylpentylthio, 3-ethyl-2-methylpentylthio, nonylthio,2-methyloctylthio, 7-methyloctylthio, 4-ethylheptylthio,3-ethyl-2-methylhexylthio, 2-ethyl-1-methylhexylthio, decylthio,1-pentylhexylthio, dodecylthio, octadecylthio, 16-methylheptadecylthio,nonadecylthio, 18-methylnonadecylthio and 3-ethyloctadecylthio groups;and

groups of formula —NR¹R², —CONR¹R² and —OCON R¹R², where R¹ and R² arethe same or different and each represents: a hydrogen atom; or an alkylgroup having from 1 to 4 carbon atoms, such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl and t-butyl groups.

Examples of the groups and atoms which may be included in substituents(b) are: alkyl groups having from 1 to 8 carbon atoms, such as themethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl,pentyl, 3-methylbutyl, 2,2-dimethylpropyl, 1,1-dimethylpropyl, hexyl,1-methylpentyl, 4-methylpentyl, heptyl, 1-methylhexyl, 2-methylhexyl,5-methylhexyl, 3-ethylpentyl, octyl, 2-methylheptyl, 6-methylheptyl,2-ethylhexyl, 2-ethyl-3-methylpentyl and 3-ethyl-2-methylpentyl groups;and hydroxy, alkoxy, aryl, aryloxy, aliphatic acyloxy, aromatic acyloxy,carboxy, alkoxycarbonyl, aryloxycarbonyl, mercapto, alkylthio, arylthio,aralkylthio, aralkyldithio, aryldithio, alkyldithio, alkylsulphinyl,arylsulphinyl, alkylsulphonyl, arylsulphonyl, cyano, aliphatic andaromatic acyl and heterocyclic groups and groups of formula —NR¹R²,—CONR¹R² and —OCON R¹R², wherein R¹ and R² are as defined above, andhalogen atoms, as exemplified in relation to substituents (a).

Substituent (c) may be an oxygen atom as part of an oxo group (>C═O)with the carbon atom to which it is attached, or it may be various othergroups and atoms as exemplified above in relation to substituents (a)and (b).

Preferred classes of compounds of the present invention include thosecompounds of formula (I) in which R₁, R₂, R₃, R₄, R₅, and R₆ areindependently hydrogen, alkyl, alkoxy, aryl and at least two of themform cycloalkyl or cycloalkenyl groups having 3 to 8 members substitutedwith alkyl, alkenyl, or alkynyl groups having from 6 to 22 carbon atomsor substituted by at least one of substituent such as hydroxy groups,protected hydroxy groups, amino groups, protected amino groups.

R₁ and R₆ are preferably selected from alkyl, cycloalkyl, cycloalkenylor —CONR¹R², where R¹ and R² are the same or different and eachrepresents an alkyl group having from 1 to 4 carbon atoms, analkylcarbonyl group having a total of from 2 to 5 carbon atoms, abenzoyl group, a substituted benzoyl group in which the substituents areselected from substituents (b), defined above; phenyl groups,substituted phenyl groups in which the substituents are selected fromsubstituents (b), defined above, heterocyclic groups having 5 or 6 ringatoms, of which 1 is a nitrogen and/or oxygen and/or sulphurhetero-atom, and halogen atoms.

X, Y is selected from O, NR′ or S, and more preferably both of X and Yare O.

More preferred classes of compounds of the present invention includethose compounds of formula (I) wherein R₂, R₄ form a single bond, R₃, R₅are hydrogen or substituted or unsubstituted alkyl having from 1 to 20carbon atoms, or substituted or unsubstituted alkenyl group 1 to 20carbon atoms, R₁ is a substituted alkyl or alkenyl group, or aryl grouphaving from 1 to 20 carbon atoms. R₁ is preferably selected from an arylgroup, which is substituted by at least one of substituents selectedfrom substituents (b), such as hydroxy groups, protected hydroxy groups,amino groups, protected amino groups, carboxy groups, protected carboxygroups, mercapto groups, protected mercapto groups, alkoxy groups havingfrom 1 to 8 carbon atoms and alkylthio groups having 1 or 2 carbonatoms.

R₆ is selected from substituents (a), and is preferably NR¹R², whereinNR¹R² represents a substituted or unsubstituted aryl, substituted orunsubstituted pyridyl, substituted or unsubstituted pyridonyl,substituted or unsubstituted pyrrolidonyl, substituted or unsubstituteduracilyl, substituted or unsubstituted piperidyl, substituted orunsubstituted piperidino, substituted or unsubstituted pyrrolidinyl,substituted or unsubstituted morpholino, substituted or unsubstitutedmorpholinyl, substituted or unsubstituted piperazinyl, substituted orunsubstituted thiomorpholino, substituted or unsubstituted dioxolanyl,cyclic imido (a group formed by removing hydrogen bound to an imido Natom). The examples of R¹ and R² include furanyl, benzofuranyl,chromenyl, pyridyl, pyrrolyl, indolyl, quinolinyl, N-alkyl pyrrolyl, 25pyridyl-N-oxide, pyrimidoyl, pyrazinyl, imidazolyl, pyrazolyl, oxazolyl,benzothiophenyl, purinyl, indolizinyl, thienyl and the like.

X, and Y represent O, NR′ or S, and preferably O.

In any of the compounds of the present invention which contains ahydroxy, amino, mercapto or carboxy group, any of these groups may beprotected by a suitable protecting group. Where the protecting group ison a compound intended for use merely as a chemical intermediate, itsnature is not critical to the invention; and any of the well knownprotecting groups may be employed. Where the resulting compound isintended for therapeutic use, the protecting group should bepharmaceutically acceptable.

Examples of hydroxy-protecting groups include: formyl, acetyl,propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl,isovaleryl, chloroacetyl, dichloroacetyl, trichloroacetyl,trifluoroacetyl. benzoyl, 4-nitrobenzoyl, 2-nitrobenzoyl,tetrahydropyran-2-yl, 3-bromotetrahydropyran-2-yl,4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yl and4-methoxytetrahydrothiopyran-4-yl, trimethylsilyl, triethylsilyl,isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl,methyldi-t-butylsilyl, triisopropylsilyl, diphenylmethylsilyl,diphenylbutylsilyl, diphenylisopropylsilyl, phenyldiisopropylsilyl,methoxymethyl, 1-ethoxyethyl, 1-(isopropoxy)ethyl, 2,2,2-trichloroethyl,benzyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl,triphenylmethyl, α-naphthyldiphenylmethyl and 9-anthrylmethyl,4-methylbenzyl, 4,4′-dimethoxytriphenylmethyl, 2-nitrobenzyl,4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl,4-cyanobenzyldiphenylmethyl.

The compounds of the invention may contain asymmetric carbon atomsand/or carbon-carbon double bonds and can, therefore, form opticaland/or cis/trans isomers. Although these are all referred to herein by asingle formula, the present invention envisages both mixtures of theisomers as well as the individual isolated isomers.

Many of the compounds of the present invention have the anti-tumoractivity referred to above. Others may be of value as intermediates inthe preparation of other compounds of the present invention, which mayhave a greater activity.

Examples of specific compounds of the present invention are thosecompounds of formula (II) (Table 1) and formula (III) (Table 2).

TABLE 1 (II)

Cpd No. R₁ R₂ R₃ R₄ R₅ R₆ 1 —CH═CHCH₂CH₂— H H —CH₂CH₂CH═CH— 2—C(CH₃)═CHCH₂CH₂— H H —CH₂—CH₂CH═C(CH₃)— 3 —C(CH₃)═CHCH₂CH(C(CH₃)═CH₂)—H H —CH(C(CH₃)═CH₂)CH₂CH═C(CH₃)— 4 —CBr(CH₃)CH(Br)CH₂CH(C(CH₃)═CH₂)— H H—CH(C(CH₃)═CH₂)CH₂CH(Br)CBr(CH₃)— 5 —CBr(CH₃)CH(Br)CH₂CH(C(CH₃)═CH₂)— HH —CH(C(CH₃)═CH₂)CH₂CH═C(CH₃)— 6 —C(CH₃)═CBrCH₂CH(C(CH₃)═CH₂)— H H—CH(C(CH₃)═CH₂)CH₂CBr═C(CH₃)— 7 —CH(CH₃)CH₂CH₂CH(C(CH₃)═CH₂)— H H—CH(C(CH₃)═CH₂)CH₂CH═C(CH₃)— 8 —CH(CH₃)CH₂CH₂CH(C(CH₃)═CH₂)— H H—CH(C(CH₃)═CH₂)CH₂CH₂CH(CH₃)— 9 —CH═C(CH₃)CH₂C((CH₃)₂)— H H—C((CH₃)₂)CH₂C(CH₃)═CH— 10 —CH═C(N(CH₃)₂)CH₂C((CH₃)₂)— H H—C((CH₃)₂)CH₂C(N(CH₃)₂)═CH— 11 —CH(Br)CH(Br)CH₂CH₂— H H—CH₂CH₂CH(Br)CH(Br)— 12 —CH═CHC((CH₃)₂)CH₂— H H —CH₂CH((CH₃)₂)CH═CH— 13—CH₂CH₂CH₂CH₂— H H —CH₂CH₂CH₂CH₂— 14 —CH₂CH₂CH(Ph)CH₂— H H—CH₂CH(Ph)CH₂CH₂— 15 —CH═C(OCH₂CH₃)CH₂CH₂— H H —CH₂CH₂C(OCH₂CH₃)═CH— 16

H H

17

H H

18

H H

19

H H

20 —CH(OH)CH(F)CH₂CH₂— H H —CH₂CH₂CH(F)CH(OH)— 21 —CH(OCH₃)CH(F)CH₂CH₂—H H —CH₂CH₂CH(F)CH(OCH₃)— 22

H H

23 —CH═CHCH₃ CH₃ H H CH₃ —CH═CHCH₃ 24 CH₃ H H H H CH₃ 25 CH₃

CH₃ 26

CH₃ H H CH₃

27

H H H H

28 —CH═C(CH₃)₂ H H H H —CH═C(CH₃)₂ 29 —CH═C(CH₃)₂ H H H —CH₂COCH═C—CH═C(CH₃)₂ (CH₃)₂ 30 —CH═CH(CH₂)₃CH₃ H H H H —CH═CH(CH₂)₃CH₃ 31

H H H H

32

H H H H

33

H H H H

34

H H H H

35

H H H H

36

H H H H

37 —CH═CHCH₂CH₂— H H H —CH═C(CH₃)₂ 38 —CH═CHCH₂CH₂— H H CH₃ —CH═CHCH₃ 39

H H H CH₃ —CH═CHCH₃ 40

H H H —CH₂CH₂CH═CH— 41

H H H —CH₂CH₂CH═CH— 42

H H H —CH₂CH₂CH═CH— 43

H H H —CH₂CH₂CH═CH— 44

H H H —CH₂CH₂CH═CH— 45

H H H —CH₂CH₂CH═CH— 46

H H H —CH₂CH₂CH═CH— 47

H H H —CH₂CH₂CH═CH— 48

H H H —CH₂CH₂CH═CH— 49

H H H —CH₂CH₂CH═CH— 50

H H H —CH₂CH₂CH═CH— 51

H H H —CH₂CH₂CH═CH— 52

H H H —CH₂CH₂CH═CH— 53

H H H —CH₂CH₂CH═CH— 54

H H H —CH₂CH₂CH═CH— 55

H H H —CH₂CH₂CH═CH— 56

H H H —CH₂CH₂CH═CH— 57

H H H —CH₂CH₂CH═CH— 58

H H H —CH₂CH₂CH═CH— 59

H H H —CH₂CH₂CH═CH— 60

H H H —CH₂CH₂CH═CH— 61

H H H —CH₂CH₂CH═CH— 62

H H H —CH₂CH₂CH═CH— 63

H H H —CH₂CH₂CH═CH— 64

H H H —CH₂CH₂CH═CH— 65

H H H —CH₂CH₂CH═CH— 66

H H H —CH₂CH₂CH═CH— 67

H H H —CH₂CH₂CH═CH— 68

H H H —CH₂CH₂CH═CH—

TABLE 2 (III)

Cpd No. R₁ R₂ X R₄ R₆ 69

H O H

70

H O H —OCH₃ 71

H O H —OCH₃ 72

H O H —OH 73

H O H —OH 74

H O H —OH 75

H O H —OCH₂CH₃ 76

H O H —OCH₂CH₃ 77

H O H —OCH₂CH₃ 78

H O H —OCH₂CH₃ 79

H O H —N(CH₃)CH₂CH₂CH₃ 80

H O H —N(CH₃)CH₂CH₂CH₃ 81

H O H —N(CH₃)CH₂CH₂CH₃ 82

H O H —N(CH₃)CH₂CH₂CH₃ 83

H O H —N(CH₃)CH₂CH₂CH₃ 84

H O H —N(CH₃)CH₂CH₂CH₃ 85

H O H —N(CH₃)CH₂CH₂CH₃ 86

H O H —N(CH₃)CH₂CH₂CH₃ 87

H O H —N(CH₃)CH₂CH₂CH₃ 88

H O H —N(CH₃)CH₂CH₂CH₃ 89

H O H —N(CH₃)CH₂CH₂CH₃ 90

H O H —N(CH₃)CH₂CH₂CH₃ 91

H O H —N(CH₃)CH₂CH₂CH₃ 92

H O H —N(CH₃)CH₂CH₂CH₃ 93

H O H —NHPh 94

H O H —NHPh 95

H O H —NHPh 96

H O H —NHPh 97

H O H —NHPh 98

H O H —NHPh 99

H O H —NHPh 100

H O H —NHPh 101

H O H —NHPh 102

H O H

103

H O H

318

H O H

104

H O H

105

H O H

106

H O H

107

H O H

108

H O H

109

H O H

110

H O H

111

H O H

112

H O H

113

H O H

114

H O H

115

H O H

116

H O H

117

H O H

118

H O H

119

H O H

120

H O H

121

H O H

122

H O H

123

H O H

124

H O H

125

H O H

126

H O H

127

H O H

128

H O H

129

H O H

130

H O H

131

H O H

132

H O H

133

H NOCH₃ H —OH 134

H NOCH₃ H —N(CH₃)CH₂CH₂CH₃ 135

H NOCH₃ H

136

H NOH H

137

H NOCH₃ H

138

H

H

139

H

H

140

H

H

141

H

H

142

H

H

143

H

H

144

H N—O— —OH 145

H N—O— —N(CH₃)CH₂CH₂CH₃ 146

H N—O— —OCH₂CH₃

The preparation of compounds of Formula (II) in this invention isillustrated in Scheme 1. The syntheses of the diketones using theoxidative coupling of lithium enolates was described by Ito et al (Itoet al. J. Ame. Chem. Soc, 1977, 1487) and Frazier et al (J. Org. Chem.,1980, 45, 5408). LDA was prepared by adding n-butyllithium to a solutionof diisopropylamine in anhydrous solvent at 0° C. and stirred for 30-60min at 0° C. The monoketone or the combination of two different ketones(for cross coupling) was added dropwise to the LDA solution at −78° C.After the mixture was stirred for 60 min at this temperature, anhydrouscopper chloride or ferric chloride solution in solvent was addeddropwise to the cold reaction solution. The resulting black mixture wasallowed to warm to room temperature and stirred for overnight. 1 N HClwas added and the mixture was extracted with organic solvents. Thecombined organic layers were washed with water, brine, dried andconcentrated to give a residue. The crude product was purified on asilica gel column or crystallized from appropriate solvents to give thedesired product.

The compounds of the present invention may be prepared by a variety ofmethods well known in the prior art for preparing diketone compoundsfrom the corresponding monoketone or the combination of differentketones.

The reaction is preferably conducted in the presence of an inertsolvent. There is no particular restriction on the nature of the solventto be employed, provided that it has no adverse effect on the reactionor on the reagents involved and that it can dissolve the reagents, atleast to some extent. Examples of suitable solvents include: aliphatichydrocarbons, such as hexane, heptane, ligroin and petroleum ether;aromatic hydrocarbons, such as benzene, toluene and xylene; halogenatedhydrocarbons, especially aromatic and aliphatic hydrocarbons, such asmethylene chloride, chloroform, carbon tetrachloride, dichloroethane,chlorobenzene and the dichlorobenzenes; esters, such as ethyl formate,ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate;ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran,dioxane. dimethoxyethane and diethylene glycol dimethyl ether; ketones,such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophoroneand cyclohexanone; nitro compounds, which may be nitroalkanes ornitroaranes, such as nitroethane and nitrobenzene; nitriles, such asacetonitrile and isobutyronitrile; amides, which may be fatty acidamides, such as formamide, dimethylformamide, dimethylacetamide andhexamethylphosphoric triamide; and sulphoxides, such as dimethylsulphoxide and sulpholane.

The reaction can take place over a wide range of temperatures, and theprecise reaction temperature is not critical to the invention. Ingeneral, we find it convenient to carry out the reaction at atemperature of from −78° C. to 50° C.

The compounds of Formula (IV) in this invention can be prepared by knownprocedure in the prior art (e.g., U.S. Pat. No. 5,618,829 and otherpatents identified above).

wherein R₁, R₂, and R₄ are defined as in formula (I).

For example, as illustrated in Scheme 2, a solution of ketone andglyoxylic acid monohydrate in acetic acid was heated under reflux overnight. Ethyl acetate was added and the mixture was washed by water,dried (Na₂SO₄) and concentrated. The crude product was purified bycolumn chromatography or crystallization to provide the desired acid inmoderate to good yield. The ester can be made by a variety of esterformation methods. For example, to a solution of the above made acid indichloromethane was added a alcohol,N-(3-dimethylaminopropyl)-N′ethylcarbodiimide hydrochloride and DMAP(cat.) and the reaction was stirred at room temperature overnight. Themixture was washed by dilute HCl (˜0.02N), water, dried (Na₂SO₄) andconcentrated. The crude product was purified by column chromatography onsilica gel to give the desired product.

The reaction is preferably conducted in the presence of an inertsolvent. There is no particular restriction on the nature of the solventto be employed, provided that it has no adverse effect on the reactionor on the reagents involved and that it can dissolve the reagents, atleast to some extent. Examples of suitable solvents include: aliphatichydrocarbons, such as hexane, heptane, ligroin and petroleum ether;aromatic hydrocarbons, such as benzene, toluene and xylene; halogenatedhydrocarbons, especially aromatic and aliphatic hydrocarbons, such asmethylene chloride, chloroform, carbon tetrachloride, dichloroethane,chlorobenzene and the dichlorobenzenes; esters, such as ethyl formate,ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate;ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran,dioxane. dimethoxyethane and diethylene glycol dimethyl ether; ketones,such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophoroneand cyclohexanone; nitro compounds, which may be nitroalkanes ornitroaranes, such as nitroethane and nitrobenzene; nitriles, such asacetonitrile and isobutyronitrile; amides, which may be fatty acidamides, such as formamide, dimethylformamide, dimethylacetamide andhexamethylphosphoric triamide; and sulphoxides, such as dimethylsulphoxide and sulpholane.

The reaction can take place over a wide range of temperatures, and theprecise reaction temperature is not critical to the invention. Ingeneral, we find it convenient to carry out the reaction at atemperature of from −50° C. to 100° C.

The compound of formula (V) in this invention can be carried out bymethods known in the art (e.g., U.S. Pat. No. 5,618,829 and otherpatents identified above).

wherein R₁, R₂, and R₄ are defined as in formula (I).

The preparations are illustrated in Scheme 3. After the carboxylic acidwas obtained from the reaction such as illustrated in Scheme 2, a amidecan be made by a variety of amide formation methods. For example, to asolution of the carboxylic acid in dichloromethane was addedN-methylpropylamine, HOBt, Et₃N and EDC at 0° C. and the mixture wasstirred at room temperature overnight. 1N HCl was added and the mixturewas extracted with dichloromethane. The combined organic layer waswashed by sodium bicarbonate, brine, dried (Na₂SO₄) and concentrated.The crude product was purified by column chromatography on silica gelgive the desired product.

The reaction is preferably conducted in the presence of an inertsolvent. There is no particular restriction on the nature of the solventto be employed, provided that it has no adverse effect on the reactionor on the reagents involved and that it can dissolve the reagents, atleast to some extent. Examples of suitable solvents include: aliphatichydrocarbons, such as hexane, heptane, ligroin and petroleum ether;aromatic hydrocarbons, such as benzene, toluene and xylene; halogenatedhydrocarbons, especially aromatic and aliphatic hydrocarbons, such asmethylene chloride, chloroform, carbon tetrachloride, dichloroethane,chlorobenzene and the dichlorobenzenes; esters, such as ethyl formate,ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate;ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran,dioxane. dimethoxyethane and diethylene glycol dimethyl ether; ketones,such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophoroneand cyclohexanone; nitro compounds, which may be nitroalkanes ornitroaranes, such as nitroethane and nitrobenzene; nitriles, such asacetonitrile and isobutyronitrile; amides, which may be fatty acidamides, such as formamide, dimethylformamide, dimethylacetamide andhexamethylphosphoric triamide; and sulphoxides, such as dimethylsulphoxide and sulpholane.

The reaction can take place over a wide range of temperatures, and theprecise reaction temperature is not critical to the invention. Ingeneral, we find it convenient to carry out the reaction at atemperature of from −50° C. to 100° C.

The compound of formula (VI) in this invention can be carried out by aprocedure known in the prior art (e.g., J. Med. Chem., 2003, 46, 2534,and other articles describing the preparation of oximes).

Wherein R′ is a hydrogen or any other groups, and R₁, R₂, R₄ and R₆ aredefined as in formula (I), preferably, R₆ is NR¹R².

The preparations are illustrated in Scheme 3. The preparation ofdicarbonyl derivatives of Formula (VI) is illustrated in Scheme 4. To asolution of dicarbonyl compound in pyridine/acetic acid was added theoxyamine at room temperature and stirred at 40° C. for 2 hours. 1N HClwas added and the mixture was extracted by ethyl acetate three times.The combined organic was washed by brine, dried (Na₂SO₄) andconcentrated. The crude product was purified on silica gel column toafford the desired product as isomers mixture or each isomer.

The reaction is preferably conducted in the presence of an inertsolvent. There is no particular restriction on the nature of the solventto be employed, provided that it has no adverse effect on the reactionor on the reagents involved and that it can dissolve the reagents, atleast to some extent. Examples of suitable solvents include: aliphatichydrocarbons, such as hexane, heptane, ligroin and petroleum ether;aromatic hydrocarbons, such as benzene, toluene and xylene; halogenatedhydrocarbons, especially aromatic and aliphatic hydrocarbons, such asmethylene chloride, chloroform, carbon tetrachloride, dichloroethane,chlorobenzene and the dichlorobenzenes; esters, such as ethyl formate,ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate;ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran,dioxane. dimethoxyethane and diethylene glycol dimethyl ether; ketones,such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophoroneand cyclohexanone; nitro compounds, which may be nitroalkanes ornitroaranes, such as nitroethane and nitrobenzene; nitriles, such asacetonitrile and isobutyronitrile; amides, which may be fatty acidamides, such as formamide, dimethylformamide, dimethylacetamide andhexamethylphosphoric triamide; and sulphoxides, such as dimethylsulphoxide and sulpholane.

The reaction can take place over a wide range of temperatures, and theprecise reaction temperature is not critical to the invention. Ingeneral, we find it convenient to carry out the reaction at atemperature of from −50° C. to 100° C.

The compounds of formula (VII) in this invention can be prepared withthe procedure in the prior art (e.g., J. Am. Chem. Soc., 2005, 127, 210,and other articles describing the preparation of isoxazoles).

The preparation of dicarbonyl derivatives of Formula (VII) isillustrated in Scheme 5. To a solution of hydroxylamine hydrochloride in1:1 t-BuOH:H₂O was added the aldehyde, followed by NaOH. After stirreduntil oxime formation was complete, Chloramine-T trihydrate was added,followed by CuSO₄.5H₂O and copper turnings. Substituted acetylene wasadded and pH was adjusted to ca. 6 by addition of a few drops of 1 MNaOH, and stirring was continued for overnight. The reaction mixture waspoured into ice/water (150 mL), and 1N HCl was added to adjust the PH˜2.The product was collected by filtration. Purification can be achieved byeither crystallization of column chromatography.

The reaction is preferably conducted in the presence of an inertsolvent. There is no particular restriction on the nature of the solventto be employed, provided that it has no adverse effect on the reactionor on the reagents involved and that it can dissolve the reagents, atleast to some extent. Examples of suitable solvents include: aliphatichydrocarbons, such as hexane, heptane, ligroin and petroleum ether;aromatic hydrocarbons, such as benzene, toluene and xylene; halogenatedhydrocarbons, especially aromatic and aliphatic hydrocarbons, such asmethylene chloride, chloroform, carbon tetrachloride, dichloroethane,chlorobenzene and the dichlorobenzenes; esters, such as ethyl formate,ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate;ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran,dioxane. dimethoxyethane and diethylene glycol dimethyl ether; ketones,such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophoroneand cyclohexanone; nitro compounds, which may be nitroalkanes ornitroaranes, such as nitroethane and nitrobenzene; nitriles, such asacetonitrile and isobutyronitrile; amides, which may be fatty acidamides, such as formamide, dimethylformamide, dimethylacetamide andhexamethylphosphoric triamide; and sulphoxides, such as dimethylsulphoxide and sulpholane.

The reaction can take place over a wide range of temperatures, and theprecise reaction temperature is not critical to the invention. Ingeneral, we find it convenient to carry out the reaction at atemperature of from −50° C. to 100° C.

The compounds of the present invention may be administered as apharmaceutical composition containing the compounds and apharmaceutically-acceptable carrier or diluent. The active materials canalso be mixed with other active materials which do not impair thedesired action and/or supplement the desired action. The activematerials, in accordance with the present invention, may be administeredby any acceptable route including, but not limited to, orally,parenterally, intravenously, intradermally, subcutaneously,intramuscularly, by an airborne delivery system, topically, in liquid orsolid form.

Oral compositions will generally include an inert diluent or an ediblecarrier. Such oral compositions may be enclosed in gelatin capsules orcompressed into tablets. For the purpose of oral therapeuticadministration, the aforesaid compounds may be incorporated withexcipients and used in the form of tablets, troches, capsules, elixirs,suspensions, syrups, wafers, chewing gums and the like.

The oral compositions may contain additional ingredients such as: abinder such as microcrystalline cellulose, gum tragacanth or gelatin; anexcipient such as starch or lactose, a disintegrating agent such asalginic acid, corn starch and the like; a lubricant such as magnesiumstearate; a glidant such as colloidal silicon dioxide; and a sweeteningagent such as sucrose or saccharin or flavoring agent such aspeppermint, methyl salicylate, or orange flavoring. When the dosage unitform is a capsule, it may additionally contain a liquid carrier such asa fatty oil. Other dosage unit forms may contain other various materialswhich modify the physical form of the dosage unit, such as, for example,a coating. Thus, tablets or pills may be coated with sugar, shellac, orother enteric coating agents. A syrup may contain, in addition to theactive ingredients, sucrose as a sweetening agent and certainpreservatives, dyes and colorings and flavors. Materials used inpreparing these various compositions should be pharmaceutically orveterinarially pure and non-toxic in the amounts used.

For the purposes of parenteral therapeutic administration, the activeingredient may be incorporated into a solution or suspension. Thesolutions or suspensions may also include the following components: asterile diluent such as water for injection, saline solution, fixedoils, polyethylene glycols, glycerine, propylene glycol or othersynthetic solvents; antibacterial agents such as benzyl alcohol ormethyl parabens; antioxidants such as ascorbic acid or sodium bisulfite;chelating agents such as ethylenediaminetetraacetic acid; buffers suchas acetates, citrates or phosphates and agents for the adjustment oftonicity such as sodium chloride or dextrose. The parenteral preparationcan be enclosed in ampoules, disposable syringes or multiple dose vialsmade of glass or plastic.

The pharmaceutical forms suitable for injectable use include sterilesolutions, dispersions, emulsions, and sterile powders. The final formshould be stable under conditions of manufacture and storage.Furthermore, the final pharmaceutical form should be protected againstcontamination and should, therefore, be able to inhibit the growth ofmicroorganisms such as bacteria or fungi. A single intravenous orintraperitoneal dose can be administered. Alternatively, a slowlong-term infusion or multiple short-term daily infusions may beutilized, typically lasting from 1 to 8 days. Alternate day dosing ordosing once every several days may also be utilized.

Sterile, injectable solutions may be prepared by incorporating acompound in the required amount into one or more appropriate solvents towhich other ingredients, listed above or known to those skilled in theart, may be added as required. Sterile injectable solutions may beprepared by incorporating the compound in the required amount in theappropriate solvent with various other ingredients as required.Sterilizing procedures, such as filtration, may then follow. Typically,dispersions are made by incorporating the compound into a sterilevehicle which also contains the dispersion medium and the required otheringredients as indicated above. In the case of a sterile powder, thepreferred methods include vacuum drying or freeze drying to which anyrequired ingredients are added.

Suitable pharmaceutical carriers include sterile water; saline,dextrose; dextrose in water or saline; condensation products of castoroil and ethylene oxide combining about 30 to about 35 moles of ethyleneoxide per mole of castor oil; liquid acid; lower alkanols; oils such ascorn oil; peanut oil, sesame oil and the like, with emulsifiers such asmono- or di-glyceride of a fatty acid, or a phosphatide, e.g., lecithin,and the like; glycols; polyalkylene glycols; aqueous media in thepresence of a suspending agent, for example, sodiumcarboxymethylcellulose; sodium alginate; polyvinylpyrrolidone); and thelike, alone, or with suitable dispensing agents such as lecithin;polyoxyethylene stearate; and the like. The carrier may also containadjuvants such as preserving stabilizing, wetting, emulsifying agentsand the like together with the penetration enhancer. In all cases, thefinal form, as noted, must be sterile and should also be able to passreadily through an injection device such as a hollow needle. The properviscosity may be achieved and maintained by the proper choice ofsolvents or excipients. Moreover, the use of molecular or particulatecoatings such as lecithin, the proper selection of particle size indispersions, or the use of materials with surfactant properties may beutilized.

In accordance with the invention, there are provided compositionscontaining geldanamycin derivatives and methods useful for the in vivodelivery of geldanamycin derivatives in the form of nanoparticles, whichare suitable for any of the aforesaid routes of administration.

In accordance with the present invention, there are providedcompositions of dicarbonyl derivative and methods useful for the in vivodelivery of dicarbonyl derivatives in the form of nanoparticles, whichare suitable for aforesaid any route administrations.

U.S. Pat. Nos. 5,916,596, 6,506,405 and 6,537,579 teach the preparationof nanoparticle from the biocompatible polymers, such as albumin. Thus,in accordance with the present invention, there are provided methods forthe formation of nanoparticles of present invention by a solventevaporation technique from an oil-in-water emulsion prepared underconditions of high shear forces (e.g., sonication, high pressurehomogenization, or the like).

The prepared nanoparticle with this invention can be administered by anyacceptable route including, but not limited to, orally, intramuscularly,transdermally, intravenously, through an inhaler or other air bornedelivery systems, and the like. When preparing the composition forinjection, particularly for intravenous delivery, the continuous phasepreferably comprises an aqueous solution of tonicity modifiers, bufferedto a pH below 7, more preferably below 6.

The prepared nanoparticles of this invention may be enclosed in a hardor soft capsule, may be compressed into tablets, or may be incorporatedwith beverages, food or otherwise into the diet. Capsules may beformulated by mixing the nanoparticle with a pharmaceutical diluentwhich is inert and inserting this mixture into a hard gelatin capsulehaving the appropriate size. If soft capsules are desired a slurry ofthe compound with an acceptable vegetable, light petroleum, or otherinert oil can be encapsulated by machine into a gelatin capsule. Thepercentage of the final composition and the preparations may, of course,be varied and may conveniently range between 1 and 90% of the weight ofthe final form, e.g., tablet. The amount in such therapeutically usefulcompositions is such that a suitable dosage will be obtained. Preferredcompositions according to the current invention are prepared so that anoral dosage unit form contains between about 5 to about 50% by weight (%w) in dosage units weighing between 50 and 1000 mg.

The lipophilic compounds in this invention will be more easily passedthrough the cell membranes and distributed tissues and cross the bloodbrain barrier. The tissue can be tissue of the Blood and Blood Formingsystem: including platelets, blood vessel wall, and bone marrow;Cardiovascular system: including heart and vascular system; Digestiveand excretory system: including alimentary tract, biliary tract, kidney,liver, pancreas and urinary tract; Endocrine system: including adrenalgland, kidney, ovary, pituitary gland, renal gland, salivary gland,sebaceous gland, testis, thymus gland and thyroid gland; Musclar system:including muscles that move the body. Reproductive System: includingbreast, ovary, penis and uterus; Respiratory system: including bronchus,lung and trachea; Skeletal system: including bones and joints; Tissue,fiber, and integumentary system: including adipose tissue, cartilage,connective tissue, cuticle, dermis, epidermis, epithelium, fascia, hairfollicle, ligament, bone marrow, melanin, melanocyte, mucous membrane,skin, soft tissue, synovial capsule and tendon.

Accordingly, the dicarbonyl derivatives of the present invention can beused in warm-blooded animals, including humans, as an anti-tumor agentagainst these kinds of tumoral diseases. The compounds may beadministered by any convenient route, for example by parenteraladministration methods, such as intravenous injection, subcutaneousinjection, intramuscular injection or by suppositories; or oraladministration by using, for example, capsules, powders or granules.

The dosage to an adult human may vary depending on the nature of thedisease, the route of administration and the administration frequencyand period. However, a daily dosage of from 1 to 100 mg in a single doseor in divided doses may be given.

For example, compositions for injection can be provided in the form ofampoules, each containing a unit dose amount, or in the form of acontainer containing multiple doses. The composition may sometimescontain additives such as emulsifiers, stabilizers and/or dispersants,and may often be in the form of a powder, which is intended to bedissolved by the pharmacist in a suitable solvent, such as apyrogen-free sterilized aqueous solvent, just before use.

In accordance with the present invention, the compounds of the presentinvention are used to treat cancers, which include but are not limitedto tumors of the nasal cavity, paranasal sinuses, nasopharynx, oralcavity, oropharynx, larynx, hypopharynx, salivary glands, andparagangliomas. The compounds of the present invention are used to treatcancers of the liver and biliary tree (particularly hepatocellularcarcinoma), intestinal cancers, particularly colorectal cancer, ovariancancer, small cell and non-small cell lung cancer, breast cancer,sarcomas (including fibrosarcoma, malignant fibrous histiocytoma,embryonal rhabdomysocarcoma, leiomysosarcoma, neuro-fibrosarcoma,osteosarcoma, synovial sarcoma, liposarcoma, and alveolar soft partsarcoma), neoplasms of the central nervous systems (particularly braincancer), lymphomas (including Hodgkin's lymphoma, lymphoplasmacytoidlymphoma, follicular lymphoma, mucosa-associated lymphoid tissuelymphoma, mantle cell lymphoma, B-lineage large cell lymphoma, Burkitt'slymphoma, and T-cell anaplastic large cell lymphoma).

The antiangiogenic treatment defined hereinbefore may be applied as asole therapy or may involve, in addition to a compound of the invention,one or more other substances and/or treatments. Such conjoint treatmentmay be achieved by way of the simultaneous, sequential or separateadministration of the individual components of the treatment. In thefield of medical oncology it is normal practice to use a combination ofdifferent forms of treatment to treat each patient with cancer. Inmedical oncology the other component(s) of such conjoint treatment inaddition to the antiangiogenic treatment defined hereinbefore may be:surgery, radiotherapy or chemotherapy. Such chemotherapy may include thefollowing categories of therapeutic agent:

(a) other antiangiogenic agents that work by different mechanisms fromthose defined hereinbefore (for example linomide, inhibitors of integrin.alpha. function, angiostatin, endostatin, razoxin, thalidomide) andincluding vascular endothelial growth factor (VEGF) receptor tyrosinekinase inhibitors (RTKIs) (for example, those described in InternationalPatent Application Publication Nos. WO 97/22596, WO 97/30035, WO97/32856 and WO 98/13354);

(b) cytostatic agents such as antioestrogens (for example tamoxifen,toremifene, raloxifene, droloxifene, iodoxyfene), progestogens (forexample megestrol acetate), aromatase inhibitors (for exampleanastrozole, tetrazole, vorazole, exemestane), antiprogestogens,antiandrogens (for example flutamide, nilutamide, bicalutamide,cyproterone acetate), LHRH agonists and antagonists (for examplegoserelin acetate, luprolide), inhibitors of testosterone5.alpha.-dihydroreductase (for example finasteride), anti-invasionagents (for example metalloproteinase inhibitors like marimastat andinhibitors of urokinase plasminogen activator receptor function) andinhibitors of growth factor function, (such growth factors include forexample epidermal growth factor (EGF), platelet derived growth factorand hepatocyte growth factor such inhibitors include growth factorantibodies, growth factor receptor antibodies, tyrosine kinaseinhibitors and serine/threonine kinase inhibitors);

(c) biological response modifiers (for example interferon);

(d) antibodies (for example edrecolomab); and

(e) antiproliferative/antineoplastic drugs and combinations thereof, asused in medical oncology, such as antimetabolites (for exampleantifolates like methotrexate, fluoropyrimidines like 5-fluorouracil,purine and adenosine analogues, cytosine arabinoside); antitumourantibiotics (for example anthracyclines like doxorubicin, daunomycin,epirubicin and idarubicin, mitomycin-C, dactinomycin, mithramycin);platinum derivatives (for example cisplatin, carboplatin); alkylatingagents (for example nitrogen mustard, melphalan, chlorambucil,busulphan, cyclophosphamide, ifosfamide, nitrosoureas, thiotepa);antimitotic agents (for example vinca alkaloids like vincristine andtaxoids like taxol, taxotere); enzymes (for example asparaginase);thymidylate synthase inhibitors (for example raltitrexed); topoisomeraseinhibitors (for example epipodophyllotoxins like etoposide andteniposide, amsacrine, topotecan, irinotecan).

In addition to their use in therapeutic medicine, the compounds offormula (I) and their pharmaceutically acceptable salts, solvates orpro-drugs are also useful as pharmacological tools in the developmentand standardization of in vitro and in vivo test systems for theevaluation of the effects of vascular damaging agents in laboratoryanimals such as cats, dogs, rabbits, monkeys, rats and mice, as part ofthe search for new therapeutic agents.

Other features of the present invention will become apparent in view ofthe following examples, which are given for illustration of theinvention and are not intended to be limiting thereof.

Example 1

This example illustrates the preparation of Compound 1. LDA was preparedby adding n-butyllithium (21.23 mL of 1.6 M solution in hexane, 34.44mmol) to a solution of diisopropylamine (4.87 mL diisopropylamine, 34.44mmol) in anhydrous THF (40 mL) at 0° C. and stirred for 30-60 min at 0°C. 3-(Dimethylamino)-5,5-dimethyl-2-cyclohexen-1-one (4.66 g, 27.86mmol) was added dropwise to the LDA solution at −78° C. After themixture was stirred for 60 min at this temperature, anhydrous ferricchloride (40 mL of 1 M solution in DMF, 40 mmol) was added dropwise tothe cold reaction solution. The resulting black mixture was allowed towarm to room temperature and stirred for overnight. 1 N HCl was addedand the mixture was extracted with dichloromethane. The combined organiclayers were washed swith water, brine, dried (NaSO₄) and concentrated togive a residue. The crude product was purified by column chromatographyon a silica gel (eluted with EtOAc:DCM:TEA:MeOH:: 80:20:5:5), and thesolvents were removed under reduced pressure to give two purple solidsof two diastereomers. Diastereomer A (17%): ¹H NMR (500 MHz, CDC1₃) δ5.00 (2H, s, COCH═C(N(CH₃)₂)CH₂), 2.94 (12H, s, N(CH₃)₂), 2.72 (2H, d,J=17.1 Hz, COCHC(CH₃)₂), 2.34, 2.01 (4H, s, d, J=17.10 Hz,═C(N(CH₃)₂)CH₂ ) 1.11, 1.02 (12H, s, s, CH₃); ESI-MS: calcd for(C20H32N2O2Na) 355, found 355 (MNa⁺). Diastereomer B (17%): ¹H NMR (500MHz, CDC1₃) δ 4.84 (2H, s, COCH═C(N(CH₃)₂)CH₂), 3.05 (2H, d, J=16.66 Hz,COCHC(CH₃)₂), 2.90 (12H, s, N(CH₃)₂), 2.27, 1.90 (4H, s, d, J=15.24),═C(N(CH₃)₂)CH₂ ) 1.11, 1.02 (12H, s, s, CH₃); ESI-MS: calcd for(C20H32N2O2Na) 355, found 355 (MNa⁺).

Example 2

This example illustrates the preparation of Compound 2. The synthesisprocedure of Compound 2 was the same as was used in the preparation ofCompound 1. Instead of using column chromatography for the purification,a crystallization method was used wherein ethyl acetate and hexanes wereused as solvents. The diastereomer mixture of Compound 2 was obtained aslight yellow solids (73%): ¹H NMR (500 MHz, CDC1₃) δ 6.60 (2H, d,J=12.00 Hz, COCH═CHC(CH₃)₂), 5.84 (2H, d, J=11.77 Hz, COCH═CHC(CH₃)₂),3.44, 3.03 (2H, dd, for major diastereomer, J=16.70 Hz, J=4.00 Hz, d,for minor diastereomer, J=17.19 Hz, COCHC(CH₃)₂), 1.93, 1.74 (2H, t, forminor diastereomer J=13.35 Hz, t, for major diastereomer, J=13.12 Hz,═CHC(CH₃)₂CH₂ ), 1.64 (2H, m, ═CHC(CH₃)₂CH₂′), 1.26, 1.20, (6H, s, formajor diastereomer, s, for minor diastereomer, CH₃), 1.16, 1.13, (6H, s,for minor diastereomer, s, for major diastereomer, CH₃); ESI-MS: calcdfor (C16H22O2Na) 269, found 269 (MNa⁺).

Example 3

This example illustrates the preparation of Compound 3. The synthesisprocedure of Compound 3 was the same as was used in the preparation ofCompound 1 and column chromatography was used for the purification(silica gel, elute: 0-15% ethyl acetate in hexanes). A mixture ofdiastereomers was obtained as white solids (41%): ¹H NMR (500 MHz,CDC1₃) δ 7.48-7.17 (10H, m, ArH), 3.32-3.10 (2H, m, CHAr), 2.62-1.00(14H, m, COCH₂ CH₂CH(Ar)CH₂ CH); ESI-MS: calcd for (C24H26O2Na) 369,found 369 (MNa⁺).

Example 4

This example illustrates the preparation of Compound 4. The synthesisprocedure of Compound 4 was the same as used in the preparation ofCompound 1. Instead of using column chromatography for the purification,a crystallization method was used wherein ethyl acetate and hexanes wereused as solvents. The diastereomer mixture of Compound 4 was obtained aswhite solids (30%): ¹H NMR (500 MHz, CDC1₃) δ 5.35, 5.34 (2H, s, s,COCH═C(OCH₂CH₃)), 4.12-3.83 (4H, m, ═C(OCH₂ CH₃)), 3.20, 2.74 (2H, m, m,COCHCH₂CH₂), 2.61-2.31 (4H, m, ═C(OCH₂CH₃)CH₂ ), 1.88-1.70 (4H, m,COCHCH₂ CH₂), 1.36-1.23 (6H, m, CH₃ ); ESI-MS: calcd for (C16H22O4Na)301, found 301 (MNa⁺).

Example 5

This example illustrates the preparation of Compound 5. The synthesisprocedure of Compound 5 was the same as used in the preparation ofCompound 1. Instead of using column chromatography for the purification,a crystallization method was used wherein ethyl acetate and hexanes wereused as solvents. The diastereomer mixture of Compound 5 was obtained aswhite solids (64%): ¹H NMR (500 MHz, CDC1₃) δ 8.04, 8.00 (2H, d, J=8.69Hz, for diastereomer A, d, J=8.77 Hz, for diastereomer B, ArH),6.84-6.80 (2H, m, ArH), 6.70 (2H, s, ArH), 3.86, 3.85 (6H, s, s, CH₃OAr), 3.60-2.89 (6H, m, COCHCH ² CH₂ ), 2.18-1.90 (4H, m, COCHCH₂ CH₂);ESI-MS: calcd for (C22H22O4Na) 373, found 373 (MNa⁺).

Example 6

This example illustrates the preparation of Compound 6. The synthesisprocedure of Compound 6 was the same as used in the preparation ofCompound 1. Instead of using column chromatography for the purification,a crystallization method was used wherein ethyl acetate and hexanes wereused as solvents. The diastereomer mixture of Compound 6 was obtained asas light yellow solids (24%): ¹H NMR (500 MHz, CDC1₃) δ 8.08, 8.03 (2H,d, J=7.86 Hz, for diastereomer A, d, J=7.84 Hz, for diastereomer B,ArH), 7.48 (2H, m, ArH), 7.32 (2H, m, ArH), 7.25 (2H, m, ArH), 3.65-2.96(6H, m, COCHCH ² CH₂ ), 2.21-1.96 (4H, m, COCHCH₂ CH₂); ESI-MS: calcdfor (C20H18O2Na) 313, found 313 (MNa⁺).

Example 7

This example illustrates the preparation of Compound 7. The synthesisprocedure of Compound 7 was the same as was used in the preparation ofCompound 1 and column chromatography was used for the purification(silica gel, elute: 0-30% ethyl acetate in hexanes). Compound 7 wasobtained as clear liquid (34%): ¹H NMR (500 MHz, CDC1₃) δ 6.94 (2H, m,CH₃CH═CHCO), 6.15 (2H, d, J=17.27 Hz, CH₃CH═CHCO), 3.12 (2H, m, COCH),1.92-1.88 (6H, m, CH ₃CH═CHCO), 1.11-0.98 (6H, m, COCHCH ₃); ESI-MS:calcd for (C12H18O2 Na) 217, found 217 (MNa⁺).

Example 8

This example illustrates the preparation of Compound 8. The synthesisprocedure of Compound 8 was the same as was used in the preparation ofCompound 1 and column chromatography was used for the purification(silica gel, elute: 10-75% ethyl acetate in hexanes). Compound 8 wasobtained as as purple color solids (14%): ¹H NMR (500 MHz, CDC1₃) ∂ 9.21(2H, d, J=8.30 Hz, ArH), 7.37 (2H, t, J=7.55 Hz, ArH), 7.07 (2H, t,J=8.47, ArH), 6.79 (2H, d, J=7.76 Hz, ArH), 3.29 (6H, s, CH ₃); ESI-MS:calcd for (C18H14N2O2) 290, found 291 (MH⁺).

Example 9

This example illustrates the preparation of Compound 9. The synthesisprocedure of Compound 9 was the same as was used in the preparation ofCompound 1. Instead of using column chromatography for the purification,a crystallization method was used wherein ethyl acetate and hexanes wereused as solvents. The diastereomer mixture of Compound 9 was obtained asas as white solids (58%): ¹H NMR (500 MHz, CDC1₃) δ 7.41-7.281 (10H, m,ArH), 5.72-5.41 (2H, m, PhCH(O)CH₂), 3.46-3.00 (2H, m, COCH), 2.81-2.00(4H, m, CH₂ ); ESI-MS: calcd for (C20H18O4Na) 345, found 345 (MNa⁺).

Example 10

This example illustrates the preparation of Compound 10. The synthesisprocedure of Compound 10 was the same as was used in the preparation ofCompound 1 and column chromatography was used for the purification(silica gel, elute: 0-15% ethyl acetate in hexanes). Compound 10 wasobtained as as white solids (48%): ¹H NMR (500 MHz, CDC1₃) δ 7.00 (2H,m, CH═C(CH₂)CO), 2.96 (4H, s, COCH₂ ), 2.26-2.20 (8H, m,CH2C(CO)═CH2CH2), 1.64-1.58 (8H, m, CH₂ CH₂ ); ESI-MS: calcd for(C16H22O2Na) 269, found 269 (MNa⁺).

Example 11

This example illustrates the preparation of Compound 11. The synthesisprocedure of Compound 11 was the same as was used in the preparation ofCompound 1 and column chromatography was used for the purification(silica gel, elute: 0-15% ethyl acetate in hexanes). Compound 11 wasobtained as light-yellow waxy solids (24%): ¹H NMR (500 MHz, CDC1₃) δ6.12 (2H, m, COCH═), 2.71 (4H, s, COCH₂ ), 2.12 (6H, d, J=0.76 Hz, CH₃), 1.88 (6H, d, J=0.90 Hz, CH₃ ); ESI-MS: calcd for (C12H18O2Na) 217,found 217 (MNa⁺).

Example 12

This example illustrates the preparation of Compound 12. The synthesisprocedure of Compound 12 was the same as was used in the preparation ofCompound 1 and column chromatography was used for the purification(silica gel, elute: 0-10% ethyl acetate in hexanes). Two diastereomersof Compound 12 were obtained as white waxy solids. Diastereomer A (19%):¹H NMR (500 MHz, CDC1₃) δ 8.06 (4H, d, J=8.00 Hz, ArH), 7.60 (2H, t,J=8.47 Hz, ArH), 7.50 (4H, t, J=7.88 Hz, ArH), 4.06 (2H, m, COCH(CH₃)),1.14, 1.11 (6H, s, s, CH₃); ESI-MS: calcd for (C18H18O2Na) 289, found289 (MNa⁺). Diastereomer B (36%): ¹H NMR (500 MHz, CDC1₃) δ 8.00 (4H, d,J=8.30 Hz, ArH), 7.55 (2H, t, J=6.88 Hz, ArH), 7.47 (4H, t, J=8.43 Hz,ArH), 3.97 (2H, m, COCH(CH₃)), 1.30, 1.27 (6H, s, s, CH₃); ESI-MS: calcdfor (C18H18O2Na) 289, found 289 (MNa⁺).

Example 13

This example illustrates the preparation of Compound 13. The synthesisprocedure of Compound 13 was similar to the preparation of Compound 1,wherein, instead of using FeCl₃, a solution of CuCl₂ in DMF was used asthe oxidative reagent. After purified by column chromatography on silicagel (elute: 0-15% ethyl acetate in hexanes), Compound 13 was obtained aspurple solids (28%): ¹H NMR (500 MHz, CDC1₃) δ 7.63 (2H, d, J=16.27 Hz,PhCH═CH), 7.56 (4H, m, Ar—H), 7.40 (6H, m, Ar—H), 6.80 (2H, d, J=16.27Hz, PhCH═CH), 3.11 (4H, s, CH₂ CH₂ ); ESI-MS: calcd for (C20H18O2Na)313, found 313 (MNa⁺).

Example 14

This example illustrates the preparation of Compound 14. The synthesisprocedure of Compound 14 was similar to the preparation of Compound 1,wherein, instead of using FeCl₃, a solution of CuCl₂ in DMF was used asthe oxidative reagent. After purified by crystallization from ethylacetate-hexanes, Compound 14 was obtained as as yellow solids (22%): ¹HNMR (500 MHz, CDC1₃) δ 7.56-7.02 (10H, m, PhCH═CH Ar—H), 6.78 (2H, d,J=16.26, PhCH═CH), 3.08 (4H, s, CH₂ CH₂ ); ESI-MS: calcd for(C20H16C12O2Na) 381, found 381 (MNa⁺).

Example 15

This example illustrates the preparation of Compound 15. The synthesisprocedure of Compound 15 was similar to the preparation of Compound 1,wherein, instead of using FeCl₃, a solution of CuCl₂ in DMF was used asthe oxidative reagent. After purified by column chromatography on silicagel (elute: 0-5% ethyl acetate in hexanes), Compound 15 was obtained asyellow liquid (39%): ¹H NMR (500 MHz, CDCl₃) δ 6.88 (2H, dt, J_(d)=16.03Hz, J_(t)=6.93 Hz, COCH═CHCH₂), 6.11 (2H, d, J=15.96 Hz, COCH═CHCH₂),2.88 (4H, s, COCH₂ CH₂ CO), 2.22 (4H, m, COCH═CHCH ₂), 1.45 (4H, m,COCH═CHCH₂CH ₂), 1.33 (4H, m, COCH═CHCH₂CH₂CH ₂), 0.90 (6H, t, J=7.35Hz, CH ₃); ESI-MS: calcd for (C16H26O2Na) 273, found 273 (MNa⁺).

Example 16

This example illustrates the preparation of Compound 16. The synthesisprocedure of Compound 16 was similar to the preparation of Compound 1,wherein, instead of using FeCl₃, a solution of CuCl₂ in DMF was used asthe oxidative reagent. After purified by column chromatography on silicagel (elute: 0-10% ethyl acetate in hexanes), Compound 16 was obtained asyellow solids (61%): ¹H NMR (500 MHz, CDC1₃) δ 7.49 (2H, dd, J=11.49 Hz,J=15.32 Hz, CH₃(CH₃)C═CHCH═CHCOCH₂), 6.10 (2H, d, J=15.31 Hz,CH₃(CH₃)C═CHCH═CHCOCH₂), 6.00 (2H, d, J=11.21 Hz,CH₃(CH₃)C═CHCH═CHCOCH₂), 2.92 (4H, s, CH₃(CH₃)C═CHCH═CHCOCH ₂), 1.90,1.88 (12H, s, s, CH ₃); ESI-MS: calcd for (C16H22O2Na) 269, found 269(MNa⁺).

Example 17

This example illustrates the preparation of Compound 17. The synthesisprocedure of Compound 17 was similar to the preparation of Compound 1,wherein, instead of using FeCl₃, a solution of CuCl₂ in DMF was used asthe oxidative reagent. After purified by column chromatography on silicagel (elute: 0-10% ethyl acetate in hexanes), Compound 17 was obtained asyellow solids (9%): ¹H NMR (500 MHz, CDC1₃) δ 7.58 (2H, d, J=16.18 Hz,PhCH═CH), 7.15 (2H, d, J=8.34 Hz, Ar—H), 7.09 (2H, s, Ar—H), 6.88 (2H,d, J=8.34 Hz, Ar—H), 6.67 (2H, d, J=16.04 Hz, PhCH═CH), 3.92 (12H, s,OCH₃), 3.09 (4H, s, CH₂ CH₂ ); ESI-MS: calcd for (C24H26O6Na) 433, found433 (MNa⁺).

Example 18

This example illustrates the preparation of Compound 18. The synthesisprocedure of Compound 18 was similar to the preparation of Compound 1,wherein, instead of using FeCl₃, a solution of CuCl₂ in DMF was used asthe oxidative reagent. After purified by column chromatography on silicagel (elute: 0-10% ethyl acetate in hexanes), Compound 18 (diastereomermixture) was obtained as white solids (11%): ¹H NMR (500 MHz, CDC1₃) δ7.55 (2H, m, Ar—H), 7.21 (2H, m, Ar—H), 6.97 (2H, m, Ar—H), 4.67-4.43(4H, m, CH ₂), 3.41-3.35 (2H, m, CH); ESI-MS: calcd for (C18H12F2O4)330, found 329 ([M−H]⁻).

Example 19

This example illustrates the preparation of Compound 19. LDA wasprepared as usual such as in the preparation of Compound 1.2-cyclohexene-1-one (1.00 mL, 10.30 mmol) and 4-Methyl-3-penten-2-one(0.47 mL, 4.12 mmol) were added concurrently to the LDA solution at −78°C. and stirred at this temperature for 30 min. then CuCl₂ in DMF (25.83mL of 0.67 M, 17.30 mmol) was added at −78° C. and stirred at thistemperature for 45 min. and then warmed up to room temperature andstirred overnight. Work up as usual and the crude product was purifiedon column, using 0-10% ethyl acetate in hexane as the eluting solvents.The desired product was obtained as yellow liquid (26%): ¹HNMR (500 MHz,CDC1₃) δ 6.94 (1H, m, CH₂CH═CHCO), 6.11 (1H, s, COCH═C(CH₃)₂), 6.02 (1H,d, J=9.94 Hz, CH₂CH═CHCO), 3.20-2.40 (3H, m, COCHCH₂CO), 2.15 (3H, s,CH3), 2.12-1.96 (2H, m, ═CHCH₂ CH₂CH), 1.89 (3H, s, CH ₃), 1.79-1.62(2H, m, ═CHCH ² CH₂ CH); ESI-MS: calcd for (C12H16O2Na) 215, found 215(MNa⁺).

Example 20

This example illustrates the preparation of Compound 20. Compound 20 wasprepared by using the same method as for the preparation of Compound 19and was obtained after purified on column (silica gel, elute: 0-10%ethyl acetate in hexane) as light yellow liquid (18%): ¹H NMR (500 MHz,CDCl₃) δ 6.92 (2H, m, CH₃CH═CHCO, CH₂CH=CHCO), 6.25 (1H, m, CH₃CH═CHCO),5.99 (1H, m, CH₂CH═CHCO), 3.31 (1H, m, CH3CH(CH)CO), 2.89-2.56 (1H, m,CH3CH(CH)CO, two diastereomers), 2.42 (2H, m, ═CHCH₂ CH₂CH), 2.03 (2H,m, ═CHCH₂CH₂ CH), 1.89 (3H, s, CH ₃), 1.17-0.99 (3H, d, d, J=7.00 Hz,J=7.00 Hz, two diastereomers); ESI-MS: calcd for (C12H16O2Na) 215, found215 (MNa⁺).

Example 21

This example illustrates the preparation of Compound 21. Compound 21 wasprepared by using the same method as for the preparation of Compound 19and was obtained after purified on column (silica gel, elute: 0-10%ethyl acetate in hexane) as light yellow waxy solids (25%): ¹H NMR (500MHz, CDC1₃) δ 7.58 (1H, d, J=16.26 Hz, PhCH═CHCO), 7.55 (2H, m, Ar—H),7.38 (3H, m, Ar—H), 6.98 (1H, m, CH₂CH═CHCO), 6.77 (1H, d, J=16.26 Hz,PhCH═CHCO), 6.05 (1H, m, CH₂CH═CHCO), 3.40 (1H, dd, J=17.26 Hz, J=4.62Hz, one of PhCH═CHCOCH ₂), 3.05 (1H, m, PhCH═CHCOCH₂CHCO) 2.57 (1H, dd,J=17.28 Hz, J=7.47 Hz, one of PhCH═CHCOCH ₂), 2.52-2.42 (2H, m,COCH═CHCH₂ CH₂), 2.17-1.08 (2H, m, COCH═CHCH ² CH ₂); ESI-MS: calcd for(C16H16O2Na) 263, found 263 (MNa⁺).

Example 22

This example illustrates the preparation of Compound 22. Compound 22 wasprepared by using the same method as for the preparation of Compound 19and was obtained after purified on column (silica gel, elute: 0-10%ethyl acetate in hexane) as orange-colored liquid (40%): ¹H NMR (500MHz, CDC1₃) δ 7.62 (1H, d, J=16.26 Hz, PhCH═CHCO), 7.55 (2H, m, Ar—H),7.38 (3H, m, Ar—H), 6.98 (1H, m, CH₃CH₂CH═CHCO), 6.72 (1H, d, J=16.26Hz, PhCH═CHCO), 6.25 (1H, m, CH₃CH₂CH═CHCO), 3.40 (1H, m,PhCH═CHCOCH₂CH(CH₃)CO), 3.24 (1H, dd, J=17.61 Hz, J=8.22 Hz, one ofPhCH═CHCOCH ₂), 2.66 (1H, dd, J=17.48 Hz, J=5.41 Hz, one of PhCH═CHCOCH₂), 1.93 (3H, d, J=6.89 Hz CH ₃CH═CH), 1.16 (3H, d, J=7.30 Hz, CH₃CH(CH₂)CO); ESI-MS: calcd for (C16H18O2Na) 265, found 265 (MNa⁺).

Example 23

This example illustrates the preparation of Compound 23. Compound 23 wasprepared by using the same method as for the preparation of Compound 19and was obtained after purified on column (silica gel, elute: 0-30%ethyl acetate in hexane) as orange solids (23%): ¹H NMR (500 MHz, CDC1₃)δ 7.55 (1H, d, J=16.19 Hz, PhCH═CHCO), 7.13 (1H, d, J=8.31 Hz, Ar—H),7.08 (1H, s, Ar—H), 6.98 (1H, m, CH₂CH═CHCO), 6,87 (1H, d, J=8.28 Hz,Ar—H), 6.66 (1H, d, J=16.22 Hz, PhCH═CHCO), 6.05 (1H, d, J=9.93 Hz,CH₂CH═CHCO), 3.90 (6H, s, OCH ₃), 3.40 (1H, dd, J=17.13 Hz, J=4.52 Hz,one of PhCH═CHCOCH ₂), 3.05 (1H, m, PhCH═CHCOCH₂CHCO), 2.55 (1H, dd,J=17.09 Hz, J=7.65 Hz, one of PhCH═CHCOCH ₂), 2.50-2.38 (211, m,COCH═CHCH₂ CH₂), 2.18-1.76 (2H, m, COCH═CHCH ² CH ₂); ESI-MS: calcd for(C18H20O4Na) 323, found 323 (MNa⁺).

Example 24

This example illustrates the preparation of Compound 24. Compound 24 wasprepared by using the same method as for the preparation of Compound 19and was obtained after purified on column (silica gel, elute: 0-20%ethyl acetate in hexane) as yellow solids (35%): ¹H NMR (500 MHz, CDC1₃)δ 7.50 (1H, d, J=16.13 Hz, PhCH═CHCO), 7.05 (1H, s, Ar—H), 7.03 (1H, d,J=8.06 Hz, Ar—H), 6.95 (1H, m, CH₂CH═CHCO), 6.82 (1H, d, J=8.02 Hz,Ar—H), 6.60 (1H, d, J=16.17 Hz, PhCH═CHCO), 6.05 (1H, d, J=10.71 Hz,CH₂CH═CHCO), 6.00 (2H, s, OCH ₂O), 3.38 (1H, dd, J=17.21 Hz, J=4.57 Hz,one of PhCH═CHCOCH ₂), 3.03 (1H, m, PhCH═CHCOCH₂CHCO), 2.50 (1H, dd,J=17.09 Hz, J=7.65 Hz, one of PhCH═CHCOCH ₂), 2.45-2.38 (2H, m,COCH═CHCH₂ CH₂), 1.92-1.72 (2H, m, COCH═CHCH₂CH ₂); ESI-MS: calcd for(C17H16O4Na) 307, found 307 (MNa⁺).

Example 25

This example illustrates the preparation of Compound 25. Compound 25 wasprepared by using the same method as for the preparation of Compound 19and was obtained after purified on column (silica gel, elute: 10-50%ethyl acetate in hexane) as as yellow solids (12%): ¹H NMR (500 MHz,CDC1₃) δ 7.52 (1H, d, J=16.13 Hz, PhCH═CHCO), 7.40 (2H, d, J=8.06 Hz,Ar—H), 6.99 (1H, m, CH₂CH═CHCO), 6.89 (2H, d, J=8.02 Hz, Ar—H), 6.62(1H, d, J=16.17 Hz, PhCH═CHCO), 6.20 (1H, s, OH), 6.05 (1H, d, J=10.71Hz, CH₂CH═CHCO), 6.00 (2H, s, OCH ₂O), 3.37 (1H, dd, J=17.21 Hz, J=4.57Hz, one of PhCH═CHCOCH ₂), 3.06 (1H, m, PhCH═CHCOCH₂CHCO), 2.50 (1H, dd,J=17.09 Hz, J=7.65 Hz, one of PhCH═CHCOCH ₂), 2.45-2.38 (2H, m,COCH═CHCH₂ CH₂), 2.17-1.78 (2H, m, COCH═CHCH ² CH ₂); ESI-MS: calcd for(C16H16O3Na) 279, found 279 (MNa⁺).

Example 26

This example illustrates the preparation of Compound 26. Compound 26 wasprepared by using the same method as for the preparation of Compound 19and was obtained after purified on column (silica gel, elute: 0-10%ethyl acetate in hexane) as orange color solids (23%): ¹H NMR (500 MHz,CDC1₃) δ 7.80 (1H, s, Ar—H), 7.72 (1H, d, J=7.98 Hz, Ar—H), 7.64 (1H, d,J=8.17 Hz, Ar—H), 7.58 (1H, d, J=16.26 Hz, PhCH═CHCO), 7.53 (1H, t,J=7.83 Hz, Ar—H), 6.98 (1H, m, CH₂CH═CHCO), 6.77 (1H, d, J=16.26 Hz,PhCH═CHCO), 6.05 (1H, m, CH₂CH═CHCO), 3.40 (1H, dd, J=17.26 Hz, J=4.62Hz, one of PhCH═CHCOCH ₂), 3.05 (1H, m, PhCH═CHCOCH₂CHCO) 2.57 (1H, dd,J=17.28 Hz, J=7.47 Hz, one of PhCH═CHCOCH ₂), 2.52-2.42 (2H, m,COCH═CHCH₂ CH₂), 2.17-1.08 (2H, m, m, COCH═CHCH ² CH ₂); ESI-MS: calcdfor (C17H15F3O2Na) 331, found 331 (MNa⁺).

Example 27

This example illustrates the preparation of Compound 27. Compound 27 wasprepared by using the same method as for the preparation of Compound 19and was obtained after purified on column (silica gel, elute: 0-25%ethyl acetate in hexane) as orange-colored syrup (15%): ¹H NMR (500 MHz,CDC1₃) δ 7.59 (1H, d, J=16.28 Hz, PhCH═CHCO), 7.55 (2H, m, Ar—H), 7.40(3H, m, Ar—H), 6.77 (1H, d, J=16.27 Hz, PhCH═CHCO), 4.16 (2H, q, J=7.15Hz, CH₃CH ₂OCO), 3.02 (2H, t, J=6.77 Hz, PhCH═CHCOCH ₂), 2.67 (2H, t,J=6.67 Hz, PhCH═CHCOCH₂CH ₂), 1.25 (3H, t, J=7.04 Hz, CH ₃CH₂OCO);ESI-MS: calcd for (C14H16O3Na) 255, found 255 (MNa⁺).

Example 28

This example illustrates the preparation of Compound 28. A solution oftrans-4-phenyl-3-butene-1-one (1.32 g) and glyoxylic acid monohydrate(0.83 g) in acetic acid (3.5 mL) was heated under reflux over night.Ethyl acetate was added and the mixture was washed by water, dried(Na₂SO₄) and concentrated. The crude product was purified by columnchromatography on silica gel (elute: 0-30% ethyl acetate in hexanes)yielding in yellow solids of Compound 28 (44%): ¹HNMR (500 MHz, CDC1₃) δ7.75 (1H, d, J=16.16 Hz, PhCH═CHCO), 7.60 (2H, m, Ar—H), 7.58 (1H, d,J=15.74 Hz, HOCOCH═CHCO), 7.42 (3H, m, Ar—H), 7.00 (1H, d, J=16.05 Hz,PhCH═CHCO), 6.84 (1H, d, J=15.75 Hz, HOCOCH═CHCO); ESI-MS: calcd for(C12H10O3) 202, found 201 ([M−H]⁻).

Example 29

This example illustrates the preparation of Compound 29. Compound 29 wasprepared by using the same method as for the preparation of Compound 28and was obtained after purified on column (silica gel, elute: 10-50%ethyl acetate in hexane) as yellow solids (39%): ¹H NMR (500 MHz, CDC1₃)δ 7.70 (1H, d, J=16.03 Hz, PhCH═CHCO), 7.58 (1H, d, J=15.69 Hz,HOCOCH═CHCO), 7.21 (1H, d, J=8.35 Hz, Ar—H), 7.12 (1H, s, Ar—H), 6.90(1H, d, J=8.34 Hz, Ar—H), 6.86 (1H, d, J=16.21 Hz, PhCH═CHCO), 6.83 (1H,d, J=15.82 Hz, HOCOCH═CHCO), 3.94 (6H, s, OCH₃); ESI-MS: calcd for(C14H14O5) 262, found 261 ([M−H]⁻).

Example 30

This example illustrates the preparation of Compound 30. Compound 30 wasprepared by using the same method as for the preparation of Compound 28and was obtained after purified on column (silica gel, elute: 10-50%ethyl acetate in hexane) as yellow solids (79%): ¹H NMR (500 MHz, CDC1₃)δ 7.65 (1H, d, J=16.00 Hz, PhCH═CHCO), 7.58 (1H, d, J=15.69 Hz,HOCOCH═CHCO), 6.88 (1H, d, J=16.08 Hz, PhCH═CHCO), 6.84 (1H, d, J=15.77Hz, HOCOCH═CHCO), 6.83 (2H, s, Ar—H), 3.90 (9H, m, 3×OCH₃); ESI-MS:calcd for (C15H16O6) 292, found 291 ([M−H]⁻).

Example 31

This example illustrates the preparation of Compound 31. To a solutionof Compound 28 (0.17 g, 0.84 mmol) in dichloromethane (10 mL) was addedethanol (0.15 mL 2.56 mmol),N-(3-dimethylaminopropyl)-N′ethylcarbodiimide hydrochloride (0.20 g,1.05 mmol) and DMAP (cat.) and the reaction was stirred at roomtemperature overnight. The mixture was washed by dilute HCl (˜0.02N),water, dried (Na₂SO₄) and concentrated. The crude product was purifiedby column chromatography on silica gel (0-10% ethyl acetate in hexanes)to give red solids of the desired product (0.075 g, 39%): ¹H NMR (500MHz, CDC1₃) δ 7.72 (1H, d, J=16.16 Hz, PhCH═CHCO), 7.60 (2H, m, Ar—H),7.48 (1H, d, J=15.74 Hz, HOCOCH═CHCO), 7.44 (3H, m, Ar—H), 7.00 (1H, d,J=16.05 Hz, PhCH═CHCO), 6.84 (1H, d, J=15.75 Hz, HOCOCH═CHCO), 4.30 (2H,q, J=7.27 Hz, OCH ₂CH₃), 1.35 (3H, t, J=7.24 Hz, OCH₂CH ₃); ESI-MS:calcd for (C14H14O3Na) 253, found 253 MNa⁺).

Example 32

This example illustrates the preparation of Compound 32. To a solutionof Compound 28 (0.15 g, 0.74 mmol) in dichloromethane (10 mL) was addedN-methylpropylamine (0.15 mL, 1.48 mmol), HOBt (0.15 g, 1.11 mmol), Et₃N(0.21 mL, 1.48 mmol) and EDC (0.19 g, 1.48 mmol) at 0° C. and themixture was stirred at room temperature overnight. 1N HCl was added andthe mixture was extracted with dichloromethane. The combined organiclayer was washed by sodium bicarbonate, brine, dried (Na₂SO₄) andconcentrated. The crude product was purified by column chromatography onsilica gel (10-50% ethyl acetate in hexanes) to give light yellow oil ofthe desired product (0.15 g, 78%): ¹H NMR (500 MHz, CDC1₃) δ 7.75 (1H,d, J=16.16 Hz, PhCH═CHCO), 7.58 and 7.42 (3H+4H, m, m 5×Ar—H,NCOCH═CHCO, NCOCH═CHCO), 6.91 (1H, d, J=16.23 Hz, PhCH═CHCO), 3.45 and3.39 (2H, t, t, J=7.45 Hz, J=7.39 Hz, for two isomers, CH₃NCH ₂CH₂CH₃),3.13 and 3.05 (3H, s, s, CH ₃NCH₂CH₂CH₃), 1.62 (2H, m, CH3NCH2CH2CH₃),0.94 (3H, t, J=7.36 Hz, CH₃NCH₂CH₂CH ₃); ESI-MS: calcd for (C16H19NO2Na)280, found 280 (MNa⁺).

Example 33

This example illustrates the preparation of Compound 33. To a solutionof Compound 28 (0.10 g, 0.49 mmol) in toluene (15 mL) was added oxalylchloride (0.15 mL, 1.48 mmol), HOBt (0.15 g, 1.11 mmol), Et₃N (0.21 mL,1.48 mmol) and EDC (0.10 ml, 1.16 mmol) at room temperature and themixture was stirred at room for 2 hours. The solvents were removed underreduced pressure. The residue was dissolved in dichloromethane andtriethylamine was added, followed by aniline at 0° C. The mixture wasstirred overnight at room temperature. 1N HCl was added and the mixturewas extracted with dichloromethane. The combined organic layer waswashed by sodium bicarbonate, brine, dried (Na₂SO₄) and concentrated.The crude product was purified by column chromatography on silica gel(0-15% ethyl acetate in hexanes) to give dark solids (5%): ESI-MS: calcdfor (C18H15NO2) 277, found 276 ([M−H]⁻).

Example 34

This example illustrates the preparation of Compound 34. Compound 34 wasprepared by using the same method as for the preparation of Compound 32and used Compound 29 as the starting material. Compound 34 was obtainedafter purified on column (silica gel, elute: 20-75% ethyl acetate inhexane) as orange oil (83%): ¹H NMR (500 MHz, CDC1₃) δ 7.70 (1H, d,J=16.15 Hz, PhCH═CHCO), 7.58 (1H, d, J=14.92, NCOCH═CHCO), 7.38 (1H, d,J=15.00, NCOCH═CHCO), 7.18 (1H, d, J=8.29 Hz, Ar—H), 7.10 (1H, s, Ar—H),6.89 (1H, d, J=8.33 Hz, Ar—H), 6.78 (1H, d, J=16.19 Hz, PhCH═CHCO), 3.93(6H, s, 2×OCH ₃), 3.45 and 3.39 (2H, t, t, J=7.50 Hz, J=7.40 Hz, for twoisomers, CH₃NCH ₂CH₂CH₃), 3.13 and 3.05 (3H, s, s, CH ₃NCH₂CH₂CH₃), 1.62(2H, m, CH3NCH2CH2CH₃), 0.94 (3H, t, J=7.36 Hz, CH₃NCH₂CH₂CH ₃); ESI-MS:calcd for (C18H23NO4Na) 340, found 340 (MNa⁺).

Example 35

This example illustrates the preparation of Compound 35. Compound 35 wasprepared by using the same method as for the preparation of Compound 32and used Compound 29 as the starting material. Compound 35 was obtainedafter purified on column (silica gel, elute: 10-50% ethyl acetate inhexane) as orange solids (28%): ¹H NMR (500 MHz, CDC1₃) δ 7.99 (1H, s,NH), 7.75-7.65 (4H, m, PhCH═CHCO, NCOCH═CHCO, NCOCH═CHCO, 1×Ar—H), 7.35(2H, m, 2×Ar—H), 7.20-7.05 (4H, m, 4×Ar—H), 6.89 (1H, d, J=8.33 Hz,1×Ar—H), 6.85 (1H, d, J=16.09 Hz, PhCH═CHCO), 3.93 (6H, s, 2×OCH ₃);ESI-MS: calcd for (C20H19NO4Na) 360, found 360 (MNa⁺).

Example 36

This example illustrates the preparation of Compound 36. Compound 36 wasprepared by using the same method as for the preparation of Compound 32and used Compound 29 as the starting material. Compound 36 was obtainedafter purified on column (silica gel, elute: MeOH/Et₃N/EtOAc: 2/2/96) asyellow oil (46%): ¹H NMR (500 MHz, CDC1₃) δ 7.70 (1H, d, J=16.15 Hz,PhCH═CHCO), 7.56 (1H, d, J=14.92, NCOCH═CHCO), 7.38 (1H, d, J=15.00,NCOCH═CHCO), 7.18 (1H, d, J=8.29 Hz, Ar—H), 7.10 (1H, s, Ar—H), 6.89(1H, d, J=8.33 Hz, Ar—H), 6.78 (1H, d, J=16.19 Hz, PhCH═CHCO), 3.95 (6H,s, 2×OCH ₃), 3.80-3.70 (4H, br, CH ₂N(CO)CH ₂), 2.51 (4H, br, CH₂N(CH₃)CH ₂), 2.37 (3H, s, CH ₃); ESI-MS: calcd for (C19H24N2O4) 344,found 345 (MH⁺).

Example 37

This example illustrates the preparation of Compound 37. Compound 37 wasprepared by using the same method as for the preparation of Compound 32and used Compound 29 as the starting material. Compound 37 was obtainedafter purified on column (silica gel, elute: MeOH/Et₃N/EtOAc: 2/2/96) asred solids (21%): ¹H NMR (500 MHz, CDC1₃) δ 8.30 (2H, d, J=5.43 Hz,2×Py-H), 7.72 (1H, d, J=16.15 Hz, PhCH═CHCO), 7.63 (1H, d, J=14.91 Hz,NCOCH═CHCO), 7.40 (1H, d, J=14.90 Hz, NCOCH═CHCO), 7.19 (1H, d, J=8.34Hz, Ar—H), 7.11 (1H, s, Ar—H), 6.90 (1H, d, J=8.37 Hz, Ar—H), 6.82 (1H,d, J=16.14 Hz, PhCH═CHCO), 6.74 (2H, d, J=6.56 Hz, 2×Py-H), 3.94 (6H, s,2×OCH ₃), 3.91-3.74 (4H, br, CH ₂N(CO)CH ₂), 3.51 (4H, br, CH ₂N(Py)CH₂); ESI-MS: calcd for (C23H25N3O4) 407, found 408 (MH⁺).

Example 38

This example illustrates the preparation of Compound 38. Compound 38 wasprepared by using the same method as for the preparation of Compound 32and used Compound 29 as the starting material. Compound 38 was obtainedafter purified on column (silica gel, elute: 10-50% ethyl acetate inhexanes) as red solids (32%): ¹H NMR (500 MHz, CDC1₃) δ 7.72 (1H, d,J=16.15 Hz, PhCH═CHCO), 7.62 (1H, d, J=14.91 Hz, NCOCH═CHCO), 7.45 (1H,d, J=14.90 Hz, NCOCH═CHCO), 7.35-6.83 (8H, m, Ar—H), 6.82 (1H, d,J=16.14 Hz, PhCH═CHCO), 3.95 (6H, s, 2×OCH ₃), 3.91-3.78 (4H, br, CH₂N(CO)CH ₂), 3.23 (4H, br, CH ₂N(Ph)CH ₂); ESI-MS: calcd for(C23H25N3O4) 407, found 408 (MH⁺).

Example 39

This example illustrates the preparation of Compound 39. Compound 39 wasprepared by using the same method as for the preparation of Compound 32and used Compound 30 as the starting material. Compound 39 was obtainedafter purified on column (silica gel, elute: MeOH/Et₃N/EtOAc: 5/2/95) asyellow syrup (70%): ¹H NMR (500 MHz, CDC1₃) δ 7.65 (1H, d, J=16.15 Hz,PhCH═CHCO), 7.54(1H, d, J=15.00, NCOCH═CHCO), 7.38 (1H, d, J=15.09,NCOCH═CHCO), 6.81 (2H, s, Ar—H), 6.82-6.80 (1H, d, J=16.18 Hz,PhCH═CHCO), 3.89-3.85 (9H, m, 3×OCH ₃), 3.75-3.61 (4H, br, CH ₂N(CO)CH₂), 2.44 (4H, br, CH ₂N(CH₃)CH ₂), 2.33 (3H, s, CH ₃); ESI-MS: calcd for(C20H26N2O5) 374, found 375 (MH⁺).

Example 40

This example illustrates the preparation of Compound 40. Compound 40 wasprepared by using the same method as for the preparation of Compound 32and used Compound 30 as the starting material. Compound 40 was obtainedafter purified on column (silica gel, elute: MeOH/Et₃N/EtOAc: 5/2/95) asorange solids (31%): ¹H NMR (500 MHz, CDC1₃) δ 8.33 (2H, d, J=6.41 Hz,2×Py-H), 7.68 (1H, d, J=16.15 Hz, PhCH═CHCO), 7.63 (1H, d, J=15.04 Hz,NCOCH═CHCO), 7.42 (1H, d, J=14.89 Hz, NCOCH═CHCO), 6.84 (1H, d, J=16.04Hz, PhCH═CHCO), 6.82 (2H, s, Ar—H), 6.68 (2H, d, J=6.50 Hz, 2×Py-H),3.90 (9H, m, 3×OCH ₃), 3.88-3.76 (4H, br, CH ₂NCO)), 3.44-3.40 (4H, br,CH ₂N(Py)CH ₂); ESI-MS: calcd for (C24H27N3O5) 437, found 438 (MH⁺).

Example 41

This example illustrates the preparation of Compound 41. To a solutionof N-(fluorophenyl)malemic acid (0.30 g, 1.43 mmol) in dichloromethane(50 mL) was added methanol (3 mL, 74.07 mmol),N-(3-dimethylaminopropyl)-N′ethylcarbodiimide hydrochloride (0.34 g,1.78 mmol) and DMAP (0.0175 g, 0.143 mmol) and the reaction was stirredat room temperature overnight. The mixture was washed by dilute HCl(˜0.02N), water, dried (Na₂SO₄) and concentrated. The crude product waspurified by column chromatography on silica gel (10-30% ethyl acetate inhexanes) to give light yellow solids of the desired product (28%): ¹HNMR (500 MHz, CDC1₃) δ 10.94 (1H, s, NH), 7.63 (2H, m, Ar—H), 7.04 (2H,m, Ar—H), 6.44 (1H, d, J=13.4, PhCH═CH), 6.23 (1H, d, J=13.4, PhCH═CH),3.86 (3H, s, CH₃ OCO); ESI-MS: calcd for (C11H10FNO3Na) 246, found 246(MNa⁺).

Example 42

This example illustrates the preparation of Compound 42. To a solutionof Compound 23 (100 mg, 0.33 mmol) in pyridine/acetic acid (5/1) wasadded methoxyaminehydrochloride (0.56 g, 6.66 mmol) at room temperatureand stirred at 40° C. for 2 hours. 1N HCl was added and the mixture wasextracted by ethyl acetate three times. The combined organic was washedby brine, dried (Na₂SO4) and concentrated. The crude product waspurified on silica gel column, using 0-20% ethyl acetate in hexane asthe eluting solvents. The desired product was obtained as colorless oilof isomers mixture (120 mg, 100%): ¹H NMR (500 MHz, CDC1₃) δ 7.20-6.07(7H, m, Ar—H, CH of all alkenes), 4.00-3.87 (12H, s, 4×OCH ₃), 3.57-2.42(3H, m, PhCH═CHCOCH ₂, PhCH═CHCOCH₂CHCO), 2.38-1.66 (4H, m, COCH═CHCH₂CH ₂); ESI-MS: calcd for (C20H26N2O4Na) 381, found 381 (MNa⁺).

Example 43

This example illustrates the preparation of Compounds 43 and 44.Compounds 43 and 44 were prepared by using the same method as for thepreparation of Compound 42 and used Compound 32 as the startingmaterial. Two isomers were obtained and separated by column on silicagel (0-20% ethyl acetate in hexane) as colorless oil. Compound 43 (45%):¹H NMR (500 MHz, CDC1₃) δ 7.54 (1H, d, J=16.00 Hz, PhCH═CHCO), 7.46 (2H,m, Ar—H), 7.36 (2H, t, J=7.11 Hz, Ar—H), 7.29 (1H, t, J=8.58 Hz, Ar—H),7.00 (1H, overlap of two d, J=16.00, J=16.00, due to two config. isomersregarding to amide, NCOCH═CHCO), 6.87 (1H, d, J=15.94, NCOCH═CHCO), 6.80(1H, d, J=16.00 Hz, PhCH═CHCO), 4.00 and 3.99 (3H, s, s, OCH ₃, due totwo config. isomers regarding to amide) 3.45 and 3.39 (2H, t, t, J=7.45Hz, J=7.36 Hz, CH₃NCH ₂CH₂CH₃, due to two config. isomers regarding toamide), 3.07 and 3.04 (3H, s, s, CH ₃NCH₂CH₂CH₃, due to two config.isomers regarding to amide), 1.62 (2H, m, CH3NCH2CH2CH₃), 0.94 (3H, t,J=7.36 Hz, CH₃NCH₂CH₂CH ₃); ESI-MS: calcd for (C17H22N2O2Na) 309, found309 (MNa⁺). Compound 44 (26%): ¹H NMR (500 MHz, CDC1₃) δ 7.50 (2H, m,PhCH═CHCO, 1×Ar—H), 7.46 (1H, d, J=15.24 Hz, NCOCH═CHCO), 7.34 (4H, m,4×Ar—H), 7.00 (1H, overlap of two d, J=16.85, J=16.82, due to twoconfig. isomers regarding to amide, PhCH═CHCO), 6.78 (1H, overlap of twod, J=15.39, due to two config. isomers regarding to amide, NCOCH═CHCO),4.03 (3H, s, s, OCH ₃, 3.45 and 3.39 (2H, t, t, J=7.45 Hz, J=7.36 Hz,due to two config. isomers regarding to amide, CH₃NCH ₂CH₂CH₃), 3.11 and3.04 (3H, s, s, due to two config. isomers regarding to amide, CH₃NCH₂CH₂CH₃), 1.62 (2H, m, CH3NCH2CH2CH₃), 0.94 (3H, t, J=7.36 Hz,CH₃NCH₂CH₂CH ₃); ESI-MS: calcd for (C17H22N2O2Na) 309, found 309 (MNa⁺).

Example 44

This example illustrates the preparation of Compound 45. Compound 45 wasprepared by using the same method as for the preparation of Compound 42and used Compound 36 as the starting material. A mixture of two isomerswas obtained and purified on column (silica gel, 0-10% TEA in ethylacetate) as light-yellow solids (10%): ¹H NMR (500 MHz, CDC1₃) δ7.56-7.48 (2H, obscured two d, J=16.00 Hz, J=15.27 Hz,PhCH═CHCOCH═CHCON, cis and trans), 7.29 (1H, d, J=16.73 Hz,PhCH═CHCOCH═CHCON, cis or trans), 7.08-6.70 (10H, m, PhCH═CHCOCH═CHCON,Ph-H, cis and trans), 6.67 (1H, d, J=16.35 Hz, PhCH═CHCOCH═CHCON, cis ortrans), 3.91-3.88 (12H, m, OCH₃, cis and trans), 3.81-3.61 (8H, m, CH₂NCO, cis and trans), 2.45 (8H, m, CH₃NCH2, cis and trans), 2.30 (6H, s,CH ₃N); ESI-MS: calcd for (C19H25N3O4) 359, found 360 (MH⁺).

Example 45

This example illustrates the preparation of Compound 46. Compound 46 wasprepared by using the same method as for the preparation of Compound 42and used Compound 36 as the starting material. A mixture of two isomerswas obtained and purified on column (silica gel, 0-5% TEA in ethylacetate) as light-yellow waxy solids (64%): ¹H NMR (500 MHz, CDC1₃) δ7.49-7.45 (2H, obscured two d, J=15.92 Hz, J=15.25 Hz,PhCH═CHCOCH═CHCON, cis and trans), 7.15 (1H, d, J=16.74 Hz,PhCH═CHCOCH═CHCON, cis or trans), 7.08-6.70 (10H, m, PhCH═CHCOCH═CHCON,Ph-H, cis and trans), 6.67 (1H, d, J=15.39 Hz, PhCH═CHCOCH═CHCON, cis ortrans), 4.03 and 3.98 (6H, s, s, NOCH ₃, cis and trans), 3.92-3.88 (12H,m, OCH₃, cis and trans), 3.75-3.46 (8H, m, CH ₂NCO, cis and trans), 2.43(8H, m, CH₃NCH2, cis and trans), 2.31 (6H, s, CH ₃N); ESI-MS: calcd for(C20H27N3O4) 373, found 374 (MH⁺).

Example 46

This example illustrates the preparation of Compound 47. Compound 47 wasprepared by using the same method as for the preparation of Compound 42and used Compound 36 as the starting material. A mixture of two isomerswas obtained and purified on column (silica gel, 0-5% TEA in ethylacetate) as light-yellow syrups (71%): ¹H NMR (500 MHz, CDC1₃) δ 7.67(1H, d, J=16.16 Hz, PhCH═CHCOCH=CHCON, cis or trans), 7.58 (1H, d,J=15.24 Hz, PhCH═CHCOCH═CHCON, cis or trans), 7.40-6.80 (22H, m,PhCH═CHCOCH═CHCON, Ph-H, cis and trans), 3.95-3.91 (12H, s, s, s, s,OCH₃, cis and trans), 3.78-3.61 (8H, m, CH ₂NCO, cis and trans), 2.45(8H, m, CH₃NCH2, cis and trans), 2.32 (6H, s, CH ₃N); ESI-MS: calcd for(C25H29N3O4Na) 458, found 458 (MNa⁺).

Example 47

This example illustrates the preparation of Compound 48. Compound 48 wasprepared by using the same method as for the preparation of Compound 42and used Compound 36 as the starting material. A mixture of two isomerswas obtained and purified on column (silica gel, 0-5% TEA in ethylacetate) as light-yellow syrups (71%): ¹H NMR (500 MHz, CDC1₃) δ7.48-6.67 (24H, m, PhCH═CHCOCH═CHCON, Ph-H, cis and trans), 5.27 and5.22 (4H, s, s PhCH ₂, cis and trans), 3.90-3.89 (12H, m, OCH₃, cis andtrans), 3.78-3.47 (8H, m, CH ₂NCO, cis and trans), 2.42 (8H, m, CH₃NCH2,cis and trans), 2.32 and 2.29 (6H, s, s, CH ₃N); ESI-MS: calcd for(C26H31N3O4) 449, found 450(MH⁺).

Example 48

This example illustrates the preparation of Compound 49. Compound 49 wasprepared by using the same method as for the preparation of Compound 42and used Compound 39 as the starting material. A mixture of two isomerswas obtained and purified on column (silica gel, 0-5% TEA in ethylacetate) as light-yellow waxy solids (55%): ¹H NMR (500 MHz, CDC1₃) δ7.48-7.43 (2H, obscured two d, J=16.00 Hz, PhCH═CHCOCH═CHCON, cis andtrans), 7.18-6.73 (6H, m, PhCH═CHCOCH═CHCON, cis and trans), 6.70 (2H,s, Ar—H, cis and trans), 6.67 (2H, s, Ar—H, cis and trans), 4.03 and4.00 (6H, s, s, NOCH ₃, cis and trans), 3.89-3.85 (18H, m, OCH₃, cis andtrans), 3.75-3.48 (8H, m, CH ₂NCO, cis and trans), 2.43 (8H, m, CH₃NCH2,cis and trans), 2.30 (6H, s, CH ₃N); ESI-MS: calcd for (C21H29N3O5) 403,found 404 (MH⁺).

Example 49

This example illustrates the preparation of Compound 50. To a solutionof hydroxylamine hydrochloride (1.45 g, 21 mmol) in 70 mL of 1:1t-BuOH:H₂O was added trans-Cinnamaldehyde (2.5 mL, 20 mmol). To this wasadded NaOH (21 mL of 1M solution, 21 mmol), and after being stirred for30 min at ambient temperature, TLC analysis indicated that oximeformation was complete. Chloramine-T trihydrate (5.88 g, 21 mmol) wasadded in small portions over 5 min, followed by CuSO₄.5H₂O (0.25 g, 1.0mmol) and copper turnings (ca. 90 mg). Propiolic acid, (1.30 mL, 21mmol) and sodium bicarbonate (1.8 g, 21 mmol) was added cocurrently. pHwas adjusted to ca. 6 by addition of a few drops of 1 M NaOH, andstirring was continued for ovrnight. The reaction mixture was pouredinto ice/water (150 mL), and 1N HCl was added to adjust the PH˜2. Theproduct was collected by filtration, redissolved, and passed through ashort plug of silica gel (50-100% ethyl acetate in hexanes) affording anoff-white solid of the desired product (3%): ¹H NMR (500 MHz, DMSO-d₆):δ 7.67-7.57 (4H, m), 7.46-7.30 (3H, m), 7.27 (1H, d, J=16.76 Hz);ESI-MS: calcd for (C12H9NO3) 215, found 214 ([M−H]⁻).

Example 50

This example illustrates the preparation of Compound 51. Compound 51 wasprepared by using the same method as for the preparation of Compound 50.After purified on column (silica gel, 0-5% ethyl acetate in hexanes),Compound 51 was obtained as white solids (21%): ¹H NMR (500 MHz, CDCl₃):δ 7.53 (2H, d, J=8.50 Hz, Ar—H), 7.41-7.35 (3H, m, Ar—H), 7.23 (1H, d,J=16.58 Hz, CH═CH), 7.18 (1H, s, CH), 7.15 (1H, d, J=16.58 Hz, CH═CH),4.45 (2H, q, J=7.01 Hz, CH ₂CH₃), 1.43 (3H, t, J=7.33 Hz, CH₂CH ₃);ESI-MS: calcd for (C14H13NO3) 243, found 244 (MH⁺).

Example 51

This example illustrates the preparation of Compound 52. Following theamide synthesis method such as the method used in the preparation ofCompound 32, from Compound 50, the desired product was prepared andpurified on column (silica gel, 0-25% ethyl acetate in hexanes) as whitesolids (18%): ¹H NMR (500 MHz, CDCl₃): δ 7.55 (2H, d, J=7.28 Hz, Ar—H),7.50-7.30 (3H, m, Ar—H), 7.22 (1H, d, J=16.64 Hz, CH═CH), 7.11 (1H, d,J=16.56 Hz, CH═CH), 7.00 and 6.98 (1H, s,s, CH cis and trans), 3.51 (2H,t, J=7.53 Hz, NCH ₂CH₂CH₃), 3.24 and 3.10 (3H, s,s, NCH ₃), 1.88-1.71(2H, m, NCH₂CH ₂CH₃), 0.99 and 0.92 (3H, t,t, J=7.42 Hz, J=7.43 Hz,NCH₂CH₂CH ₃); ESI-MS: calcd for (C16H18N2O2) 270, found 93 (MNa⁺).

Example 52 In Vitro Evaluation

This example showed the in vitro growth inhibition experiments for thecompounds in the invention on MX-1 (human breast carcinoma) cells. Thecytotoxicity assay was quantitated using the Promega CellTiter Blue CellViability Assay. Briefly, cells (5000 cells/well) were plated onto96-well microtiter plates in RPMI 1640 medium supplemented with 10% FBSand incubated at 378 C in a humidified 5% CO₂ atmosphere. After 24 h,cells were exposed to various concentrations of compound in DMSO andcultured for another 72 h. 100 ul of media were removed and 20 ul ofPromega CellTiter Blue reagent were added to each well and shaken tomix. After 4 hours of incubation at 37° C. in a humidified 5% CO2atmosphere, the plates were read at 544ex/620em. The fluorescenceproduced is proportional to the number of viable cells. After plottingfluorescence produced against drug concentration, the 10₅₀ wascalculated as the half-life of the resulting non-linear regression. Thedata showed in Table 1.

TABLE 1 IC₅₀ dicarbonyl derivatives ID Chemical Structure IC₅₀ (μM) 1

>1000 2

56.83 3

29.73 4

>1000 5

>1000 6

>1000 7

2.63 8

351.68 9

472.47 10

>1000 11

10.29 12

>1000 13

37.88 14

55.67 15

7.99 16

16.24 17

73.09 18

>1000 19

1.04 20

0.52 21

0.42 22

2.07 23

0.17 24

0.70 25

0.16 26

2.59 27

77.49 28

3.96 29

29.00 30

34.21 31

2.17 32

0.39 33

3.25 34

0.28 35

0.89 36

0.17 37

0.12 38

0.25 39

0.80 40

0.48 41

120.97 42

128.34 43

171.11 44

171.11 45

371.15 46

481.99 47

8.73 48

23.36 49

>1000 50

>1000 51

533.2 52

194.6

Obviously, numerous modifications and variations of the presentinvention are possible in light of the above teachings. It is thereforeto be understood that within the scope of the appended claims, theinvention may be practiced otherwise than as specifically describedherein.

All references, including publications, patent applications, andpatents, cited herein are hereby incorporated by reference to the sameextent as if each reference were individually and specifically indicatedto be incorporated by reference and were set forth in its entiretyherein.

The use of the terms “a” and “an” and “the” and similar referents in thecontext of describing the invention (especially in the context of thefollowing claims) are to be construed to cover both the singular and theplural, unless otherwise indicated herein or clearly contradicted bycontext. The terms “comprising,” “having,” “including,” and “containing”are to be construed as open-ended terms (i.e., meaning “including, butnot limited to,”) unless otherwise noted. Recitation of ranges of valuesherein are merely intended to serve as a shorthand method of referringindividually to each separate value falling within the range, unlessotherwise indicated herein, and each separate value is incorporated intothe specification as if it were individually recited herein. All methodsdescribed herein can be performed in any suitable order unless otherwiseindicated herein or otherwise clearly contradicted by context. The useof any and all examples, or exemplary language (e.g., “such as”)provided herein, is intended merely to better illuminate the inventionand does not pose a limitation on the scope of the invention unlessotherwise claimed. No language in the specification should be construedas indicating any non-claimed element as essential to the practice ofthe invention.

Preferred embodiments of this invention are described herein, includingthe best mode known to the inventors for carrying out the invention.Variations of those preferred embodiments may become apparent to thoseof ordinary skill in the art upon reading the foregoing description. Theinventors expect skilled artisans to employ such variations asappropriate, and the inventors intend for the invention to be practicedotherwise than as specifically described herein. Accordingly, thisinvention includes all modifications and equivalents of the subjectmatter recited in the claims appended hereto as permitted by applicablelaw. Moreover, any combination of the above-described elements in allpossible variations thereof is encompassed by the invention unlessotherwise indicated herein or otherwise clearly contradicted by context.

1-17. (canceled)
 18. A method for treating a disease or condition in amammal characterized by undesired cellular proliferation orhyperproliferation comprising identifying the mammal afflicted with saiddisease or condition and administering to said afflicted mammal acomposition comprising the compound or pharmaceutically acceptable saltthereof having the formula (I)

wherein R₁, R₂, R₃, R₄, R₅, and R₆ are independently a hydrogen atom oran alkyl, alkenyl, alkynyl, or aryl comprising 1 to 30 carbon atoms andwhich is unsubstituted or substituted by at least one of hydroxy, cyano,mercapto, halogen, —OR₇, SR₇, —NR₇R₈, —CONR₇R₈, or —OCONR₇R₈, wherein R₇and R₈ are a hydrogen atom; an alkyl, alkenyl, or alkynyl comprising 1to 20 carbon atoms; a cyclic or heterocyclic group comprising 5 or 6ring atoms of which from 0 to 3 are nitrogen, oxygen, sulphur or acombination thereof of hetero-atoms, said cyclic or heterocyclic groupbeing unsubstituted or substituted by at least one of hydroxy, cyano,mercapto, halogen, or an alkyl group comprising 1 to 6 carbon atoms; andX and Y are respectively O, NR₇ or S, wherein when X and Y are O, and ifR₂, R₄ are hydrogen, R₁-R₃ or both R₁-R₃ and R₅-R₆ form a cyclic or anacyclic alkenyl; when X and Y are O, and if R₂, R₄ form a single bond,R₁ is

wherein Ar is an aryl or heteroaryl.
 19. The method of claim 18,comprising administering to said afflicted mammal a compositioncomprising compound or pharmaceutically acceptable salt thereof havingthe formula (I) wherein X and Y are O, and R₆ is NR₇R₈.
 20. The methodof claim 18, comprising administering to said afflicted mammal acomposition comprising compound or pharmaceutically acceptable saltthereof having the formula (I) wherein, wherein X and Y are O.
 21. Themethod of claim 18, comprising administering to said afflicted mammal acomposition comprising compound or pharmaceutically acceptable saltthereof, wherein the compound has the following formula:


22. The method of claim 21, wherein in said compound R₇ and R₈ areC₁-C₁₀ alkyl and C₆-C₁₀ aryl, respectively.
 23. The method of claim 18,comprising administering to said afflicted mammal a compositioncomprising compound or pharmaceutically acceptable salt thereof, whereinthe compound has the following formula:


24. The method of claim 23, wherein in said compound R₇ and R₈ areC₁-C₁₀ alkyl and C₆-C₁₀ aryl, respectively.
 25. The method of claim 24,wherein in said compound X is H, 3-OMe, 4-OMe, or 3,4-di-OMe.
 26. Themethod of claim 18, wherein said disease or condition is cancer.
 27. Themethod of claim 18, wherein said composition is administered as a singleintravenous dose, a single intraperitoneal dose, a slow long-terminfusion, multiple short-term daily infusions, and combinations thereof.28. The method of claim 18, wherein said cancer is selected from thegroup consisting of cancers of the liver and biliary tree, intestinalcancers, colorectal cancer, ovarian cancer, small cell and non-smallcell lung cancer, breast cancer, sarcomas, fibrosarcoma, malignantfibrous histiocytoma, embryonal rhabdomysocarcoma, leiomysosarcoma,neuro-fibrosarcoma, osteosarcoma, synovial sarcoma, liposarcoma,alveolar soft part sarcoma, neoplasms of the central nervous systems,brain cancer, and lymphomas, including Hodgkin's lymphoma,lymphoplasmacytoid lymphoma, follicular lymphoma, mucosa-associatedlymphoid tissue lymphoma, mantle cell lymphoma, B-lineage large celllymphoma, Burkitt's lymphoma, and T-cell anaplastic large cell lymphoma,and combinations thereof.
 29. The method of claim 27, further comprisingadministering to said afflicted mammal a said second active agentselected from the group consisting of taxane, doxorubicin, 5-FU andother anticancer drugs.